{"data":[{"id":2734,"name":"An overview of current drugs and prophylactic vaccines for coronavirus disease 2019 (COVID-19).","author":"Alagheband Bahrami, Armina Azargoonjahromi, Ali Sadraei, Samin Aarabi, Aryan Payandeh, Zahra Rajabibazl, Masoumeh","doi":"10.1186\/s11658-022-00339-3","abstract":"Designing and producing an effective vaccine is the best possible way to reduce the burden and spread of a disease. During the coronavirus disease 2019 (COVID-19) pandemic, many large pharmaceutical and biotechnology companies invested a great deal of time and money in trying to control and combat the disease. In this regard, due to the urgent need, many vaccines are now available earlier than scheduled. Based on their manufacturing technology, the vaccines available for COVID-19 (severe acute respiratory syndrome coronavirus 2 (SAR-CoV2)) infection can be classified into four platforms: RNA vaccines, adenovirus vector vaccines, subunit (protein-based) vaccines, and inactivated virus vaccines. Moreover, various drugs have been deemed to negatively affect the progression of the infection via various actions. However, adaptive variants of the SARS-CoV-2 genome can alter the pathogenic potential of the virus and increase the difficulty of both drug and vaccine development. In this review, along with drugs used in COVID-19 treatment, currently authorized COVID-19 vaccines as well as variants of the virus are described and evaluated, considering all platforms.Graphical abstract:","type":"Review","database":"PMC","created":"2022-05-12"},{"id":2729,"name":"Multifaceted role of natural sources for COVID-19 pandemic as marine drugs.","author":"Rahman, MominurIslam, RezaulShohag, SheikhHossain, EmonShah, Muddasershuvo, Shakil khanKhan, HosnearaChowdhury, Arifur RahmanBulbul, Israt JahanHossain, SarowarSultana, SharifaAhmed, MuniruddinAkhtar, Muhammad FurqanSaleem, AmmaraRahman, Habibur","doi":"10.1007\/s11356-022-20328-5","abstract":"COVID-19, which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread over the world, posing a global health concern. The ongoing epidemic has necessitated the development of novel drugs and potential therapies for patients infected with SARS-CoV-2. Advances in vaccination and medication development, no preventative vaccinations, or viable therapeutics against SARS-CoV-2 infection have been developed to date. As a result, additional research is needed in order to find a long-term solution to this devastating condition. Clinical studies are being conducted to determine the efficacy of bioactive compounds retrieved or synthesized from marine species starting material. The present study focuses on the anti-SARS-CoV-2 potential of marine-derived phytochemicals, which has been investigated utilizing in in\u00a0silico, in vitro, and in vivo models to determine their effectiveness. Marine-derived biologically active substances, such as flavonoids, tannins, alkaloids, terpenoids, peptides, lectins, polysaccharides, and lipids, can affect SARS-CoV-2 during the viral particle\u2019s penetration and entry into the cell, replication of the viral nucleic acid, and virion release from the cell; they can also act on the host\u2019s cellular targets. COVID-19 has been proven to be resistant to several contaminants produced from marine resources. This paper gives an overview and summary of the various marine resources as marine drugs and their potential for treating SARS-CoV-2. We discussed\u00a0at numerous natural compounds as marine drugs\u00a0generated from natural sources for treating COVID-19 and controlling the current pandemic scenario.","type":"Review","database":"PMC","created":"2022-05-03"},{"id":2716,"name":"Antiviral Efficacy of Selected Natural Phytochemicals against SARS-CoV-2 Spike Glycoprotein Using Structure-Based Drug Designing.","author":"Bandar Hamad Aloufi, Mejdi Snoussi, Abdel Moneim E Sulieman, ","doi":"10.3390\/molecules27082401","abstract":"SARS-CoV-2 is a highly virulent coronavirus that first surfaced in late 2019 and has since created a pandemic of the acute respiratory sickness known as \"coronavirus disease 2019\" (COVID-19), posing a threat to human health and public safety. S-RBD is a coronaviral protein that is essential for a coronavirus (CoV) to bind and penetrate into host cells. As a result, it has become a popular pharmacological target. The goal of this study was to find potential candidates for anti-coronavirus disease 2019 (COVID-19) drugs by targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-RBD with novel bioactive compounds and molecular interaction studies of 15,000 phytochemicals belonging to different flavonoid subgroups. A spike protein crystal structure attached to the ACE2 structure was obtained from the PDB database. A library of 15,000 phytochemicals was made by collecting compounds from different databases, such as the Zinc-database, PubChem-database, and MPD3-database. This library was docked against a receptor binding domain of a spike glycoprotein through the Molecular Operating Environment (MOE). The top drug candidates Phylloflavan, Milk thistle, Ilexin B and Isosilybin B, after virtual screening, were selected on the basis of the least binding score. Phylloflavan ranked as the top compound because of its least binding affinity score of -14.09 kcal\/mol. In silico studies showed that all those compounds showed good activity and could be used as an immunological response with no bioavailability issues. Absorption, distribution, metabolism, excretion and a toxicological analysis were conducted through SwissADME. Stability and effectiveness of the docked complexes were elucidated by performing the 100 ns molecular dynamic simulation through the Desmond package.","type":"Research","database":"PubMed","created":"2022-04-07"},{"id":2715,"name":"Recent Advances in Passive Immunotherapies for COVID-19: The Evidence-Based Approaches and Clinical Trials.","author":"Farhangnia, PooyaDehrouyeh, ShivaSafdarian, Amir RezaFarahani, Soheila VasheghaniGorgani, MelikaRezaei, NimaAkbarpour, MahzadDelbandi, Ali-Akbar","doi":"10.1016\/j.intimp.2022.108786","abstract":"In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, causing a global pandemic called COVID-19. Currently, there is no definitive treatment for this emerging disease. Global efforts resulted in developing multiple platforms of COVID-19 vaccines, but their efficacy in humans should be wholly investigated in the long-term clinical and epidemiological follow-ups. Despite the international efforts, COVID-19 vaccination accompanies challenges, including financial and political obstacles, serious adverse effects (AEs), the impossibility of using vaccines in certain groups of people in the community, and viral evasion due to emerging novel variants of SARS-CoV-2 in many countries. For these reasons, passive immunotherapy has been considered a complementary remedy and a promising way to manage COVID-19. These approaches are based on reduced inflammation due to inhibiting cytokine storm phenomena, immunomodulation, preventing acute respiratory distress syndrome (ARDS), viral neutralization, and decreased viral load. This article highlights passive immunotherapy and immunomodulation approaches in managing and treating COVID-19 patients and discusses relevant clinical trials (CTs).","type":"Review","database":"PMC","created":"2022-04-20"},{"id":2708,"name":"Efficacy and Safety of Fixed Combination of Hydroxychloroquine with Azithromycin Versus Hydroxychloroquine and Placebo in Patients with Mild COVID-19: Randomized, double blind, Placebo controlled trial","author":" I. A. Roy-Garcia, M. Moreno-Noguez, R. Rivas-Ruiz, M. Zapata-Tarres, M. Perez-Rodriguez, M. A. Ortiz-Zamora, G. Navarro-Susano, L. Guzman-Rivas, L. R. Garcia-Cortes, I. Palma-Lara, P. Gutierrez-Catrellon,","doi":"10.1101\/2022.04.06.22273531","abstract":"To determine the efficacy and safety of fixed combination of hydroxychloroquine\/azithromycin (HCQ+AZT) compared to hydroxychloroquine (HCQ) alone or placebo in mild COVID-19 outpatients to avoid hospitalization.Materials and methods                                                                            This randomized, parallel, double-blind clinical trial included male and female patients aged 18 and 76 years non COVID vaccinated, who were diagnosed with mild COVID-19 infection. All patients underwent liver and kidney profile test, as well as a health questionnaire and clinical revision to document that they did not have uncontrolled comorbidities. They were randomly assigned to one of the three treatment arms: 1) hydroxychloroquine with azithromycin 200 mg\/250 mg every 12 hours for five days followed by hydroxychloroquine 200 mg every 12 hours for 5 days; 2) hydroxychloroquine 200 mg every 12 hours for ten days; or 3) placebo every 12 hours for ten days. The primary outcome of the study was hospitalization, while the secondary outcomes were disease progression, pneumonia, use of supplemental oxygen, and adverse events. This study was registered in clinicaltrials.gov with the NCT number of 04964583.ResultsA total of 92 participants were randomized. Of whom, 30 received HCQ+AZT, 31 received HCQ, and 31 received placebo. The median age was 37 years, 27.2% of the participants had comorbidities, and the global incidence of hospitalization was 2.2%. The incidence of hospitalization was 6.7% (2\/30) in the HCQ+AZT group compared to the HCQ or placebo groups, in which there were no hospitalizations. Progression of disease was higher in the HCQ group [RR=3.25 (95% CI, 1.19-8.87)] compared with placebo group. There was no statistical difference between the HCQ+AZT group and the placebo group in progression of disease. The incidence of pneumonia was 30% in the HCQ+AZT group, 32.2% in the HCQ group, and 9.6% in the placebo group (HCQ + AZT vs Placebo; p=0.06). There was a significant risk of pneumonia versus placebo only in the HCQ group [RR=3.33 (95% CI, 1.01-10.9)]. Supplemental oxygen was required by 20% (6\/30) of the patients in the HCQ+AZT group, 6.4 (2\/31) of the patients in the HCQ group, and 3.2% (1\/31) of the patients in the placebo group,[(HCQ + AZT vs Placebo; p=0.100), (HCQ vs Placebo, p=0.610)]. There was no statistical difference between groups for negative test (PCR) on day 11. The most frequent adverse events were gastrointestinal symptoms. No lengthening of the QT interval was observed in patients receiving HCQ+AZT or HCQ.ConclusionThe use of HCQ+AZT does not decrease the risk of hospitalization in patients with mild COVID-19. The use of HCQ increases the risk of progression and pneumonia.","type":"Research","database":"MedRxiv","created":"2022-04-15"},{"id":2705,"name":"Computational prediction of the molecular mechanism of statin group of drugs against SARS-CoV-2 pathogenesis.","author":"Ghosh, DipanjanGhosh Dastidar, DebabrataRoy, KamaleshGhosh, ArnabMukhopadhyay, DebanjanSikdar, NilabjaBiswas, Nidhan K.Chakrabarti, GopalDas, Amlan","doi":"10.1038\/s41598-022-09845-y","abstract":"Recently published clinical data from COVID-19 patients indicated that statin therapy is associated with a better clinical outcome and a significant reduction in the risk of mortality. In this study by computational analysis, we have aimed to predict the possible mechanism of the statin group of drugs by which they can inhibit SARS-CoV-2 pathogenesis. Blind docking of the critical structural and functional proteins of SARS-CoV-2 like RNA-dependent RNA polymerase, M-protease of 3-CL-Pro, Helicase, and the Spike proteins ( wild type and mutants from different VOCs) were performed using the Schrodinger docking tool. We observed that fluvastatin and pitavastatin showed fair, binding affinities to RNA polymerase and 3-CL-Pro, whereas fluvastatin showed the strongest binding affinity to the helicase. Fluvastatin also showed the highest affinity for the SpikeDelta and a fair docking score for other spike variants. Additionally, molecular dynamics simulation confirmed the formation of a stable drug-protein complex between Fluvastatin and target proteins. Thus our study shows that of all the statins, fluvastatin can bind to multiple target proteins of SARS-CoV-2, including the spike-mutant proteins. This property might contribute to the potent antiviral efficacy of this drug.","type":"Research","database":"PMC","created":"2022-04-13"},{"id":2704,"name":"A multicenter, open-label, randomized, proof-of-concept phase II clinical trial to assess the efficacy and safety of icatibant in patients infected with SARS-CoV-2 (COVID-19) and admitted to hospital units without invasive mechanical ventilation: study protocol (ICAT-COVID).","author":"Pierre Malchair, Aurema Otero, Jordi Giol, Xavier Solanich, Thiago Carnaval, Alonso Fern\u00e1ndez-Nistal, Ana S\u00e1nchez-Gabriel, Carmen Montoto, Ramon Lleonart , Sebasti\u00e1n Videla","doi":"10.1186\/s13063-022-06219-7","abstract":"Background\r\nCOVID-19 has quickly become a global pandemic with a substantial number of deaths and is a considerable burden for healthcare systems worldwide. Although most cases are paucisymptomatic and limited to the viral infection-related symptoms, some patients evolve to a second phase, with an impaired inflammatory response (cytokine storm) that may lead to acute respiratory distress syndrome and death. This is thought to be caused by increased bradykinin synthesis.\r\n\r\nMethods\r\nICAT-COVID is a multicenter, randomized, open-label, proof-of-concept phase II clinical trial assessing the clinical efficacy and safety of adding icatibant to the standard of care in patients hospitalized with COVID-19 without invasive mechanical ventilation. Patients hospitalized with a confirmed COVID-19 pneumonia diagnosis (RT-PCR or antigen test \u2264\u200910\u2009days prior to randomization, and radiographic evidence of pulmonary infiltrates), rated \u201c4\u201d or \u201c5\u201d on the WHO\u2019s clinical status scale, are eligible. Patients will be randomized on a 1:1 ratio to either standard of care-plus-icatibant (experimental group) or to standard of care alone (control group). The experimental group will receive 30\u2009mg of icatibant subcutaneously 3 times a day for 3\u2009days (for a total of 9 doses). The expected sample size is 120 patients (60 per group) from 2 sites in Spain. Primary outcomes are the efficacy and safety of Icatibant. The main efficacy outcome is the number of patients reaching grades \u201c2\u201d or \u201c1\u201d on the WHO scale within 10\u2009days of starting treatment. Secondary outcomes include \u201clong-term efficacy\u201d: number of patients discharged who do not present COVID-19-related relapse or comorbidity up until 28\u2009days after discharge, and mortality.\r\n\r\nDiscussion\r\nIcatibant, a bradykinin type 2 receptor antagonist with proven effectiveness and safety against hereditary angioedema attacks, may be beneficial for COVID-19 patients by inhibiting bradykinin\u2019s action on endothelial cells and by inhibiting the SARS-CoV-2 M protease. Our working hypothesis is that treatment with standard of care-plus-icatibant is effective and safe to treat patients infected with SARS-CoV-2 admitted to hospital for pneumonia without invasive mechanical ventilation.","type":"Research","database":"PubMed","created":"2022-04-11"},{"id":2698,"name":"Anti-Fungal Drug Anidulafungin Inhibits SARS-CoV-2 Spike-Induced Syncytia Formation by Targeting ACE2-Spike Protein Interaction.","author":"Ahamad, ShahzaibAli, HashimSecco, IlariaGiacca, MauroGupta, Dinesh","doi":"10.3389\/fgene.2022.866474","abstract":"Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters target cells by binding to the ACE2 receptor via its spike (S) glycoprotein. We used molecular docking-based virtual screening approaches to categorize potential antagonists, halting ACE2-spike interactions by utilizing 450 FDA-approved chemical compounds. Three drug candidates (i.e., anidulafungin, lopinavir, and indinavir) were selected, which show high binding affinity toward the ACE2 receptor. The conformational stability of selected docked complexes was analyzed through molecular dynamics (MD) simulations. The MD simulation trajectories were assessed and monitored for ACE2 deviation, residue fluctuation, the radius of gyration, solvent accessible surface area, and free energy landscapes. The inhibitory activities of the selected compounds were eventually tested in-vitro using Vero and HEK-ACE2 cells. Interestingly, besides inhibiting SARS-CoV-2 S glycoprotein induced syncytia formation, anidulafungin and lopinavir also blocked S-pseudotyped particle entry into target cells. Altogether, anidulafungin and lopinavir are ranked the most effective among all the tested drugs against ACE2 receptor-S glycoprotein interaction. Based on these findings, we propose that anidulafungin is a novel potential drug targeting ACE2, which warrants further investigation for COVID-19 treatment.","type":"Research","database":"PMC","created":"2022-03-24"},{"id":2687,"name":"Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial","author":" J. Sasson, A. N. Donlan, J. Z. Ma, H. Haughey, R. Coleman, U. Nayak, A. J. Mathers, P. E. H. Jackson, S. K. Heysell, J. M. Sturek, W. Petri,","doi":"10.1101\/2022.03.30.22273194","abstract":"Background A profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19 to prevent respiratory decline or death. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess the safety and efficacy of dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, in those hospitalized with COVID-19.\r\n\r\nMethods We conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days, with collection of clinical outcomes, adverse events and immunologic biomarkers at multiple time points throughout the study period. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days analyzed in logistic regression.\r\n\r\nResults Forty eligible subjects were enrolled from June 23, 2021 through November 11, 2021. There was no difference in adverse events nor in proportion of patients alive and free of mechanical ventilation at day 28 between study treatment groups. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate: 89.5% of subjects in the dupilumab group were alive compared to 76.2% in the placebo group (adjusted HR 0.05, 95% CI: 0.0-0.72, p=0.03). There was a trend toward reduction in ICU admission in the dupilumab group compared to the placebo group (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09-2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade through analysis of immune biomarkers at multiple study time points.\r\n\r\nConclusions Dupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. Blockade of type 2 immunity offers promise as a novel treatment for COVID-19.","type":"Research","database":"MedRxiv","created":"2022-04-04"},{"id":2679,"name":"Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial","author":" F. Ader, M. Bouscambert Duchamp, M. Hites, N. Peiffer Smadja, J. Poissy, D. Belhadi, A. Diallo, C. Delmas, J. Saillard, A. Dechanet, C. Fougerou, M. P. Le, G. Peytavin, N. Mercier, P. Velou, S. Tubiana, X. Lescure, E. Faure, S. Nseir, J. C. Richard, F. Wallet, F. Goehringer, B. Lefevre, A. Kimmoun, F. Raffi, B. Gaborit, J. Reignier, J. P. Lanoix, C. Andrejak, Y. Zerbib, F. Bani Sadr, B. Mourvilliers, F. Danion, Y. Ruch, R. Clere Jehl, V. Le Moing, K. Klouche, K. Lacombe, G. Martin Blondel, F. ","doi":"10.1101\/2022.03.30.22273206","abstract":"Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and\/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring. Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948, EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir\/ritonavir, lopinavir\/ritonavir and IFN-beta-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420). At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62\/420 (14.8%) and 72\/423 (17.0%); Not hospitalized, limitation on activities: 126\/420 (30%) and 135\/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56\/420 (13.3%) and 31\/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75\/420 (17.9%) and 65\/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16\/420 (3.8%) and 16\/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64\/420 (15.2%) and 80\/423 (18.9%); Death: 21\/420 (5%) and 24\/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147\/410, 35.9%, versus control, n=138\/423, 32.6%, p=0.29). Interpretation: Remdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15. Funding: European Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER \"European Regional Development Fund\", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.","type":"Research","database":"MedRxiv","created":"2022-03-30"},{"id":2673,"name":"Can anti-parasitic drugs help control COVID-19?","author":"Panahi, YasinDadkhah, MasoomehTalei, SahandGharari, ZahraAsghariazar, VahidAbdolmaleki, ArashMatin, SomayehMolaei, Soheila","doi":"10.2217\/fvl-2021-0160","abstract":"Novel COVID-19 is a public health emergency that poses a serious threat to people worldwide. Given the virus spreading so quickly, novel antiviral medications are desperately needed. Repurposing existing drugs is the first strategy. Anti-parasitic drugs were among the first to be considered as a potential treatment option for this disease. Even though many papers have discussed the efficacy of various anti-parasitic drugs in treating COVID-19 separately, so far, no single study comprehensively discussed these drugs. This study reviews some anti-parasitic recommended drugs to treat COVID-19, in terms of function and in vitro as well as clinical results. Finally, we briefly review the advanced techniques, such as artificial intelligence, that have been used to find effective drugs for the treatment of COVID-19.","type":"Review","database":"PMC","created":"2022-02-27"},{"id":2671,"name":"COVID-19 at a Glance: An Up-to-Date Overview on Variants, Drug Design and Therapies.","author":"Iacopetta, DomenicoCeramella, JessicaCatalano, AlessiaSaturnino, CarmelaPellegrino, MicheleMariconda, AnnaluisaLongo, PasqualeSinicropi, Maria StefaniaAquaro, Stefano","doi":"10.3390\/v14030573","abstract":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronavirus family which caused the worldwide pandemic of human respiratory illness coronavirus disease 2019 (COVID-19). Presumably emerging at the end of 2019, it poses a severe threat to public health and safety, with a high incidence of transmission, predominately through aerosols and\/or direct contact with infected surfaces. In 2020, the search for vaccines began, leading to the obtaining of, to date, about twenty COVID-19 vaccines approved for use in at least one country. However, COVID-19 continues to spread and new genetic mutations and variants have been discovered, requiring pharmacological treatments. The most common therapies for COVID-19 are represented by antiviral and antimalarial agents, antibiotics, immunomodulators, angiotensin II receptor blockers, bradykinin B2 receptor antagonists and corticosteroids. In addition, nutraceuticals, vitamins D and C, omega-3 fatty acids and probiotics are under study. Finally, drug repositioning, which concerns the investigation of existing drugs for new therapeutic target indications, has been widely proposed in the literature for COVID-19 therapies. Considering the importance of this ongoing global public health emergency, this review aims to offer a synthetic up-to-date overview regarding diagnoses, variants and vaccines for COVID-19, with particular attention paid to the adopted treatments.","type":"Review","database":"PMC","created":"2022-03-09"},{"id":2664,"name":"A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval.","author":"Ashour, Nada AAbo Elmaaty, AymanSarhan, Amany AElkaeed, Eslam BMoussa, Ahmed MErfan, Ibrahim AliAl-Karmalawy, Ahmed A","doi":"10.2147\/DDDT.S354841","abstract":"The rising outbreak of SARS-CoV-2 continues to unfold all over the world. The development of novel effective antiviral drugs to fight against SARS-CoV-2 is a time cost. As a result, some specific FDA-approved drugs have already been repurposed and authorized for COVID-19 treatment. The repurposed drugs used were either antiviral or non-antiviral drugs. Accordingly, the present review thoroughly focuses on the repurposing efficacy of these drugs including clinical trials experienced, the combination therapies used, the novel methods followed for treatment, and their future perspective. Therefore, drug repurposing was regarded as an effective avenue for COVID-19 treatment. Recently, molnupiravir is a prodrug antiviral medication that was approved in the United Kingdom in November 2021 for the treatment of COVID-19. On the other hand, PF-07321332 is an oral antiviral drug developed by Pfizer. For the treatment of COVID-19, the PF-07321332\/ritonavir combination medication is used in Phase III studies and was marketed as Paxlovid. Herein, we represented the almost history of combating COVID-19 from repurposing to the recently available oral anti-SARS-CoV-2 candidates, as a new hope to end the current pandemic.","type":"Review","database":"PMC","created":"2022-03-14"},{"id":2662,"name":"An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?","author":" A. Kurdi, N. Weir, T. Mueller,","doi":"10.1101\/2022.03.20.22272664","abstract":"Backgrounds Evidence from several meta-analyses are still controversial about the effects of angiotensin-converting enzyme inhibitors (ACEIs)\/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes. Purpose Umbrella review of systematic reviews\/meta-analysis to provide comprehensive assessment of the effect of ACEIs\/ARBs on COVID-19 related outcomes by summarising the currently available evidence. Data Source Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1st February 2021. Study Selection Systematic reviews with meta-analysis that evaluated the effect of ACEIs\/ARBs on COVID-19 related clinical outcomes Data Extraction Two reviewers independently extracted the data and assessed studies risk of bias using AMSTAR 2 Critical Appraisal Tool. Data Synthesis Pooled estimates were combined using the random-effects meta-analyses model including several sub-group analyses. Overall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs\/ARBs use and each of death (OR=0.80, 95%CI=0.75-0.86; I2=51.9%), death\/ICU admission as composite outcome (OR=0.86, 95%CI=0.80-0.92; I2=43.9%), severe COVID-19 (OR=0.86, 95%CI=0.78-0.95; I2=68%), and hospitalisation (OR=1.23, 95%CI=1.04-1.46; I2= 76.4%). The significant reduction in death\/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR=0.63, 95%CI=0.47-0.84) and were of moderate quality (OR=0.74, 95%CI=0.63-0.85). Limitations The effect of unmeasured confounding could not be ruled out. Only 21.3% (n=10) of the studies were of moderate quality. Conclusion: Collective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs\/ARBs use and reduction in death and death\/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs\/ARBs therapy in patients with COVID-19. Registration The study protocol was registered in PROSPERO (CRD42021233398). Funding Source None","type":"Review","database":"MedRxiv","created":"2022-03-20"},{"id":2656,"name":"Mechanism of Action of Small-Molecule Agents in Ongoing Clinical Trials for SARS-CoV-2: A Review.","author":"Zhao, LeiLi, SongZhong, Wu","doi":"10.3389\/fphar.2022.840639","abstract":"Since the first reports from December 2019, COVID-19 caused an overwhelming global pandemic that has affected 223 countries, seriously endangering public health and creating an urgent need for effective drugs to treat SARS-CoV-2 infection. Currently, there is a lack of safe, effective, and specific therapeutic drugs for COVID-19, with mainly supportive and symptomatic treatments being administered to patients. The preferred option for responding to an outbreak of acute infectious disease is through drug repurposing, saving valuable time that would otherwise be lost in preclinical and clinical research, hastening clinical introduction, and lowering treatment costs. Alternatively, researchers seek to design and discover novel small-molecule candidate drugs targeting the key proteins in the life cycle of SARS-CoV-2 through an in-depth study of the infection mechanism, thus obtaining a number of candidate compounds with favorable antiviral effects in preclinical and clinical settings. There is an urgent need to further elucidate the efficacy and mechanism of action of potential anti-SARS-CoV-2 small-molecule drugs. Herein, we review the candidate small-molecule anti-SARS-CoV-2 drugs in ongoing clinical trials, with a major focus on their mechanisms of action in an attempt to provide useful insight for further research and development of small-molecule compounds against SARS-CoV-2 infection.","type":"Review","database":"PMC","created":"2022-02-24"},{"id":2646,"name":"13 cis retinoic acid improved the outcomes of COVID-19 patients. A randomized clinical trial","author":" M. R. Elkazzaz, Y. Esam-Eldin Abo-Amer, A. Ahmed, T. Hayadar,","doi":"10.1101\/2022.03.05.22271959","abstract":"The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. Given the urgency of the COVID-19 pandemic, the clinical investigation of approved drugs is a promising alternative to find a timely effective treatment. In this randomized trial, we investigated the activity of both oral and aerosolized 13 cis retinoic acid in the treatment of SARS-COV-2 added to standard of care treatment in patients with COVID-19 versus standard of care treatment alone. This was a randomized controlled trial conducted at Kafrelsheikh University\u2019s Quarantine Hospitals, Egypt. After obtaining informed consent, forty patients with a confirmed diagnosis of COVID-19 were enrolled in the study. They were randomly assigned to one of two groups: Group I; 20 patients received aerosolized and oral 13 cis retinoic acid plus standard of care treatment (13 cis RA group) and Group II; 20 patients received only standard care treatment as a control group. The two groups were age and gender matched. There was no statistically significant difference between them in any of the baseline characteristics or laboratory parameters. The results showed that there was a high significant difference between the two groups regarding intensive care unit (ICU) admission, mortality and improvement (P<0.05). Only 10.52 % of patients in the 13 cis retinoic acid group needed ICU admission compared to 28.57 % in the control arm. There was no mortality in the 13 cis retinoic acid group, whereas about 14.35% were died in the group II. All patients who received 13 cis retinoic acid noticed a high improvement (P<0.001), and the mean value for clinical improvement was 16.3\u00b14.5 days. There was no significant difference regarding the laboratory parameters before and after 14 days of treatment in the group of patients received the standard of care treatment (P=0.66). Univariate logistic regression analysis showed overall mortality was significantly related to the patient\u2019s age, serum ferritin, C-reactive protein, oxygen saturation, the presence of diabetes mellitus, obesity, and abdominal pain. We conclude that 13 cis retinoic acid is a promising drug in the treatment of patients with COVID-19 infection, when added to the standard of care treatment.","type":"Research","database":"MedRxiv","created":"2022-03-07"},{"id":2638,"name":"Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis","author":" P. W. Horby, J. R. Emberson, M. Mafham, M. Campbell, L. Peto, G. Pessoa-Amorim, E. Spata, N. Staplin, C. Lowe, D. R. Chadwick, C. Brightling, R. Stewart, P. Collini, A. Ashish, C. A. Green, B. Prudon, T. Felton, A. Kerry, J. K. Baillie, M. H. Buch, J. N. Day, S. N. Faust, T. Jaki, K. Jeffery, E. Juszczak, M. Knight, W. S. Lim, A. Montgomery, A. Mumford, K. Rowan, G. Thwaites, R. Haynes, M. J. Landray,","doi":"10.1101\/2022.03.02.22271623","abstract":"Background: We evaluated the use of baricitinib, a Janus kinase (JAK) 1\/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. Findings: Between 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0.87; 95% CI 0.77-0.98; p=0.026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. Interpretation: In patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.","type":"Research","database":"MedRxiv","created":"2022-03-02"},{"id":2623,"name":"An open-label randomized, controlled trial of the effect of lopinavir\/ritonavir, lopinavir\/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19 - Final results from the DisCoVeRy trial","author":" F. ADER, N. PEIFFER-SMADJA, J. POISSY, M. BOUSCAMBERT-DUCHAMP, D. BELHADI, A. DIALLO, C. DELMAS, J. SAILLARD, A. DECHANET, N. MERCIER, A. DUPONT, T. ALFAIATE, F.-X. LESCURE, F. RAFFI, F. GOEHRINGER, A. KIMMOUN, S. JAUREGUIBERRY, J. REIGNIER, S. NSEIR, F. DANION, R. CLERE-JEHL, K. BOUILLER, J.-C. NAVELLOU, V. TOLSMA, A. CABIE, C. DUBOST, J. COURJON, S. LEROY, J. MOOTIEN, R. GACI, B. MOURVILLIER, E. FAURE, V. POURCHER, S. GALLIEN, O. LAUNAY, K. LACOMBE, J.-P. LANOIX, A. MAKINSON, G. MARTIN-BLOND","doi":"10.1101\/2022.02.16.22271064","abstract":"Objectives We evaluated the clinical, virological and safety outcomes of lopinavir\/ritonavir, lopinavir\/ritonavir-interferon (IFN)-beta-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and\/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. Methods We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir\/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. Results The intention-to-treat population included 593 participants (lopinavir\/ritonavir, n=147; lopinavir\/ritonavir-IFN-beta-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir\/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir\/ritonavir-IFN-beta-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir\/ritonavir-containing arms. Conclusion In adults hospitalized for COVID-19, lopinavir\/ritonavir, lopinavir\/ritonavir-IFN-beta-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.","type":"Research","database":"MedRxiv","created":"2022-02-20"},{"id":2622,"name":"Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients With Mild to Moderate COVID-19: A Phase 2 Randomized Clinical Trial.","author":"Cairns, Dana M.Dulko, DorothyGriffiths, Jeffrey K.Golan, YoavCohen, TheodoraTrinquart, LudovicPrice, Lori LynBeaulac, Kirthana R.Selker, Harry P.","doi":"10.1001\/jamanetworkopen.2021.44942","abstract":"Importance  Oral anthelmintic niclosamide has potent in vitro antiviral activity against SARS-CoV-2. Repurposed niclosamide could be a safe and efficacious COVID-19 therapy.\r\n\r\nObjective  To investigate whether niclosamide decreased SARS-CoV-2 shedding and duration of symptoms among patients with mild to moderate COVID-19.\r\n\r\nDesign, Setting, and Participants  This randomized, placebo-controlled clinical trial enrolled individuals testing positive for SARS-CoV-2 by polymerase chain reaction with mild to moderate symptoms of COVID. All trial participants, investigators, staff, and laboratory personnel were kept blind to participant assignments. Enrollment was among individuals reporting at Tufts Medical Center and Wellforce Network in Massachusetts for outpatient COVID-19 testing. The trial opened to accrual on October 1, 2020; the last participant enrolled on April 20, 2021. Trial exclusion criteria included hospitalization at time of enrollment or use of any experimental treatment for COVID-19, including vaccination. Enrollment was stopped before attaining the planned sample size when COVID-19 diagnoses decreased precipitously in Massachusetts. Data were analyzed from July through September 2021.\r\n\r\nInterventions  In addition to receiving current standard of care, participants were randomly assigned on a 1:1 basis to receive niclosamide 2 g by mouth daily for 7 days or identically labeled placebo at the same dosing schedule.\r\n\r\nMain Outcomes and Measures  Oropharyngeal and fecal samples were self-collected for viral shedding measured by reverse-transcriptase\u2013polymerase-chain-reaction on days 3, 7, 10, and 14, and an additional fecal sample was collected on day 21. A telehealth platform was developed to conduct remote study visits, monitor symptoms, and coordinate sample collection via couriers. The primary end point was the proportion of participants with viral clearance in respiratory samples at day 3 based on the intention-to-treat sample. Mean times to viral clearance and symptom resolution were calculated as restricted mean survival times and accounted for censored observations.\r\n\r\nResults  Among 73 participants, 36 individuals were enrolled and randomized to niclosamide and 37 individuals to placebo. Participant characteristics were similar across treatment groups; among 34 patients receiving placebo and 33 patients receiving niclosamide in the intention-to-treat sample, mean (SD) age was 36.0 (13.3) years vs 36.8 (12.9) years and there were 21 (61.8%) men vs 20 (60.6%) men. The overall mean (SD) age was 36.4 (13.0) years. For the primary end point, 66.67% (95% CI, 50.74% to 81.81%) of participants receiving niclosamide and 55.88% (95% CI, 40.27% to 72.73%) of participants receiving placebo had oropharyngeal SARS-CoV-2 clearance at day 3 (P\u2009=\u2009.37). Among 63 participants with symptoms, niclosamide did not significantly shorten symptom duration, which was 12.01 (95% CI, 8.82 to 15.2) days in the niclosamide group vs 14.61 (95% CI, 11.25 to 17.96) days in the placebo group (mean difference, \u22122.6 [95% CI, \u22127.23 to 2.03] days). Niclosamide was well-tolerated; the most commonly reported adverse events in the placebo and niclosamide groups were headaches (11 patients [32.4%] vs 7 patients [21.2%]; P\u2009=\u2009.31) and cough (8 patients [23.5%] vs 7 patients [21.2%]; P\u2009=\u2009.82).\r\n\r\nConclusions and Relevance  In this randomized clinical trial, there was no significant difference in oropharyngeal clearance of SARS-CoV-2 at day 3 between placebo and niclosamide groups. Confirmation in larger studies is warranted.","type":"Research","database":"PMC","created":"2022-02-08"},{"id":2614,"name":"Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19","author":" D. M. Lowe, L.-A. K. Brown, K. Chowdhury, S. Davey, P. Yee, F. Ikeji, A. Ndoutoumou, D. Shah, A. Lennon, A. Rai, A. A. Agyeman, A. Checkley, N. Longley, H.-M. Dehbi, N. Freemantle, J. Breuer, J. F. Standing, FLARE Investigators,","doi":"10.1101\/2022.02.11.22270775","abstract":"Background: Early antiviral treatment is effective for COVID-19 but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on SARS-CoV-2 viral load trajectory when administered early. Methods: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2x2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg\/100mg twice daily on Day 1, followed by 200mg\/50mg four times daily on Days 2-7); favipiravir plus lopinavir-ritonavir placebo; lopinavir-ritonavir plus favipiravir placebo; or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. ClinicalTrials.gov: NCT04499677. Findings: Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo and placebo-only arms, we recruited 61, 59, 60 and 60 participants and analysed 55, 56, 55 and 58 participants respectively who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had decreased by 0.57 log10 (95% CI -1.21 to 0.07, p=0.08) and in the lopinavir-ritonavir+placebo arm by 0.18 log10 (95% CI -0.82 to 0.46, p=0.58) more than in the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p=0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% vs 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p=0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm. Interpretation: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations.","type":"Research","database":"MedRxiv","created":"2022-02-14"},{"id":2612,"name":"Drug repurposing against SARS-CoV-2 using computational approaches.","author":"Kumar, SumitKovalenko, SvitlanaBhardwaj, ShakshiSethi, AaftaabYu. Gorobets, NikolayDesenko, Sergey M.PoonamRathi, Brijesh","doi":"10.1016\/j.drudis.2022.02.004","abstract":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated a critical need for treatments to reduce morbidity and mortality associated with this disease. However, traditional drug development takes many years, which is not practical solution given the current pandemic. Therefore, a viable option is to repurpose existing drugs. The structural data of several proteins vital for the virus became available shortly after the start of the pandemic. In this review, we discuss the importance of these targets and their available potential inhibitors on the basis of computational approaches. Among the hits identified by computational approaches, 35 candidates were suggested for further evaluation, among which ten drugs are in clinical trials (Phase III and IV) for treating Coronavirus 2019 (COVID-19).Teaser: We provide a snapshot of existing drugs explored using computational approaches to search for rapid and effective solutions against SARS-CoV-2.","type":"Review","database":"PMC","created":"2022-02-09"},{"id":2608,"name":"Innovative Randomized Phase 1 Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir","author":" R. S. P. Singh, S. S. Toussi, F. Hackman, P. L. Chan, R. Rao, R. Allen, L. Van Eyck, S. Pawlak, E. P. Kadar, F. Clark, H. Shi, A. S. Anderson, M. Binks, S. Menon, G. Nucci, A. Bergman,","doi":"10.1101\/2022.02.08.22270649","abstract":"Background: COVID-19 is a continued leading cause of hospitalization and death. Safe and efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, SARS-CoV-2 Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. Methods: We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase 1 study . Two interleaving single-ascending dose (SAD) cohorts were evaluated in a 3-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir\/ritonavir twice daily (BID) dosing was evaluated over 10 days in 5 parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase 2\/3 clinical trials were supported by integrating modelling and simulations of SAD\/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). Results: In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir\/ritonavir was safe and well tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir\/ritonavir dose and regimen for phase 2\/3 trials (300\/100 mg BID), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients and prevent development of severe disease, hospitalization, and death. Conclusions: An innovative and seamless trial design expedited establishment of phase 1 safety and pharmacokinetics of nirmatrelvir\/ritonavir, enabling high confidence in phase 2\/3 dose selection and accelerated pivotal trials initiation. NCT04756531","type":"Research","database":"MedRxiv","created":"2022-02-09"},{"id":2603,"name":"N-acylethanolamine acid amide hydrolase is a novel target for drugs against SARS-CoV-2 and Zika virus","author":" M. Lai, V. La Rocca, R. Amato, E. Iacono, c. filipponi, E. Catelli, L. Bogani, R. Fonnesu, g. lottini, A. De Carli, A. Mengozzi, S. Masi, P. Quaranta, P. G. Spezia, G. Freer, P. Lenzi, F. Fornai, D. Piomelli, M. Pistello,","doi":"10.1101\/2022.02.08.479661","abstract":"Several compounds have been tested against SARS-CoV-2; at present, COVID-19 treatments decrease the deleterious inflammatory response and acute lung injury. However, the best therapeutic response would be expected by combining anti-inflammatory properties, while concomitantly blocking viral replication. These combined effects should drastically reduce both infection rate and severe complications induced by novel SARS-CoV-2 variants. Therefore, we explored the antiviral potency of a class of anti-inflammatory compounds that inhibit the N-Acylethanolamine acid amidase (NAAA). This enzyme catalyzes the hydrolysis of palmitoylethanolamide (PEA), a bioactive lipid that mediates anti-inflammatory and analgesic activity through the activation of peroxisome proliferator receptor- (PPAR-). Similarly, this pathway is likely to be a significant target to impede viral replication since PPAR- activation leads to dismantling of lipid droplets, where viral replication of Flaviviruses and Coronaviruses occurs.","type":"Research","database":"BioRxiv","created":"2022-02-08"},{"id":2602,"name":"The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters","author":" L. Miorin, C. E. Mire, S. Ranjbar, A. J. Hume, J. Huang, N. A. Crossland, K. M. White, M. Laporte, T. Kehrer, V. Haridas, E. Moreno, A. Nambu, S. Jangra, A. Cupic, M. Dejosez, K. A. Abo, A. E. Tseng, R. B. Werder, R. Rathnasinghe, T. Mutetwa, I. Ramos, J. Sainz de Aja, C. Garcia de Alba Rivas, M. Schotsaert, R. B. Corley, J. V. Falvo, A. Fernandez-Sesma, C. Kim, J.-F. Rossignol, A. A. Wilson, T. Zwaka, D. N. Kotton, E. M&uumlhlberger, A. Garc&iacutea-Sastre, A. E. Goldfeld,","doi":"10.1101\/2022.02.08.479634","abstract":"A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.","type":"Research","database":"BioRxiv","created":"2022-02-08"},{"id":2601,"name":"The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and X-ray diffraction at room temperature","author":" G. J. Correy, D. W. Kneller, G. Phillips, S. Pant, S. Russi, A. E. Cohen, G. Meigs, J. M. Holton, S. Gahbauer, M. C. Thompson, A. Ashworth, L. Coates, A. Kovalevsky, F. Meilleur, J. S. Fraser,","doi":"10.1101\/2022.02.07.479477","abstract":"The NSP3 macrodomain of SARS CoV 2 (Mac1) removes ADP-ribosylation post-translational modifications, playing a key role in the immune evasion capabilities of the virus responsible for the COVID-19 pandemic. Here, we determined neutron and X-ray crystal structures of the SARS-CoV-2 NSP3 macrodomain using multiple crystal forms, temperatures, and pHs, across the apo and ADP-ribose-bound states. We characterize extensive solvation in the Mac1 active site, and visualize how water networks reorganize upon binding of ADP-ribose and non-native ligands, inspiring strategies for displacing waters to increase potency of Mac1 inhibitors. Determining the precise orientations of active site water molecules and the protonation states of key catalytic site residues by neutron crystallography suggests a catalytic mechanism for coronavirus macrodomains distinct from the substrate-assisted mechanism proposed for human MacroD2. These data provoke a re-evaluation of macrodomain catalytic mechanisms and will guide the optimization of Mac1 inhibitors.","type":"Research","database":"BioRxiv","created":"2022-02-08"},{"id":2598,"name":"Antidepressant and Antipsychotic Drugs Reduce Viral Infection by SARS-CoV-2 and Fluoxetine Shows Antiviral Activity Against the Novel Variants in vitro.","author":"Fred, Senem MerveKuivanen, SuviUgurlu, HasanCasarotto, Plinio CabreraLevanov, LevSaksela, KalleVapalahti, OlliCastr\u00e9n, Eero","doi":"10.3389\/fphar.2021.755600","abstract":"Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2\/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our in vitro findings.","type":"Research","database":"PMC","created":"2022-01-18"},{"id":2596,"name":"A Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19","author":" J. H. Shrimp, J. Janiszewski, C. Z. Chen, M. Xu, K. M. Wilson, S. C. Kales, P. E. Sanderson, P. Shinn, Z. Itkin, H. Guo, M. Shen, C. Klumpp-Thomas, S. G. Michael, W. Zheng, A. Simeonov, M. D. Hall,","doi":"10.1101\/2022.02.04.479134","abstract":"SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allowed for rapid movement of existing clinical candidates and therapies into human clinical trials to be tested as COVID-19 therapies. One effective antiviral treatment strategy used early in symptom onset is to prevent viral entry. SARS-CoV-2 enters ACE2-expressing cells when the receptor-binding domain of the spike protein on the surface of SARS-CoV-2 binds to ACE2 followed by cleavage at two cut sites on the spike protein. TMPRSS2 has a protease domain capable of cleaving the two cut sites; therefore, a molecule capable of inhibiting the protease activity of TMPRSS2 could be a valuable antiviral therapy. Initially, we used a fluorogenic high-throughput screening assay for the biochemical screening of 6030 compounds in NCATS annotated libraries. Then, we developed an orthogonal biochemical assay that uses mass spectrometry detection of product formation to ensure that hits from the primary screen are not assay artifacts from the fluorescent detection of product formation. Finally, we assessed the hits from the biochemical screening in a cell-based SARS-CoV-2 pseudotyped particle entry assay. Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2.","type":"Research","database":"BioRxiv","created":"2022-02-06"},{"id":2595,"name":"Results From the REsCue Trial: A Randomized Controlled Trial with Extended-Release Calcifediol in Symptomatic Outpatients with COVID-19.","author":" C. W. Bishop, A. Ashfaq, J. Z. Melnick, E. Vazquez-Escarpanter, J. A. Fialkow, S. A. Strugnell, J. Choe, K. Kalantar-Zadeh, N. C. Federman, D. Ng, J. S. Adams,","doi":"10.1101\/2022.01.31.22270036","abstract":"Importance The benefit of vitamin D treatment for coronavirus disease 2019 (COVID-19) remains unclear.\r\n\r\nObjective To investigate the effect of raising serum total 25-hydroxyvitamin D (25D) to 50-100 ng\/mL with oral extended-release calcifediol (ERC) on time to symptom resolution in mild to moderate COVID-19.\r\n\r\nDesign, Setting, and Participants A multicenter, randomized, double-blind, placebo-controlled study evaluated treatment of 160 outpatients with COVID-19 diagnosed between November 2020 and October 2021.\r\n\r\nInterventions Patients were treated for 4 weeks with ERC (30 mcg\/capsule; 300 mcg on Days 1-3 and 60 mcg on Days 4-27) or placebo.\r\n\r\nOutcome Measures Primary endpoints were raising serum 25D to \u226550 ng\/mL at Day 14 and resolution time for five aggregated symptoms. Secondary endpoints included resolution time for aggregated and individual symptoms as a function of serum 25D and changes in clinical biomarkers.\r\n\r\nResults 171 subjects randomized, 160 treated and 134 (65 ERC and 69 placebo) retained. Average age was 43 (range: 18-71); 59% female, 92% White, 80% Hispanic, 7% African-American, 1% Other, 76% overweight, 40% obese, 26% comorbidities, mean baseline 25D of 37\u00b11 (SE) ng\/mL. ERC increased mean 25D to 82\u00b14 ng\/mL (p<0.001) by Day 7; 88% of subjects attained a level \u226550 ng\/mL; the placebo group trended lower. Resolution time for five aggregated symptoms was unchanged by ERC given that two composite non-respiratory symptoms responded poorly. Prespecified analyses showed that respiratory symptoms tended to resolve earlier when serum 25D levels reached \u226450 ng\/mL, but statistical significance was limited by small sample size and non-compliance: 25D increased in seven placebo subjects (unauthorized supplementation) and none occurred in five ERC subjects (failure to dose). A post-hoc composite of three respiratory symptoms (trouble breathing, chest congestion and dry or hacking cough) resolved 3.0 days faster when 25D was elevated at Days 7 and 14 (p<0.05); chest congestion resolved 4.0 days faster with 25D increases of \u226525 ng\/mL (p<0.05). Safety concerns including hypercalcemia were absent with ERC treatment.\r\n\r\nConclusions and Relevance ERC was effective in increasing serum 25D in outpatients with COVID-19, which may have accelerated resolution of respiratory symptoms suggesting mitigation of COVID-19 pneumonia risk, findings which warrant further study.","type":"Research","database":"MedRxiv","created":"2022-02-04"},{"id":2586,"name":"Doxycycline for the prevention of progression of COVID-19 to severe disease requiring intensive care unit (ICU) admission: a randomized, controlled, open-label, parallel group trial (DOXPREVENT.ICU)","author":" R. Dhar, J. Kirkpatrick, L. Gilbert, A. Khanna, M. M. Modi, R. K. Chawla, S. Dalal, V. N. Maturu, M. Stern, O. T. Keppler, R. Djukanovic, S. D. Gadola,","doi":"10.1101\/2022.01.30.22269685","abstract":"Background: After admission to hospital, COVID-19 progresses in a substantial proportion of patients to critical disease that requires intensive care unit (ICU) admission. Methods: In a pragmatic, non-blinded trial, 387 patients aged 40-90 years were randomised to receive treatment with SoC plus doxycycline (n=192) or SoC only (n=195). The primary outcome was the need for ICU admission as judged by the attending physicians. Three types of analyses were carried out for the primary outcome: Intention to treat (ITT) based on randomisation; Per protocol (PP), excluding patients not treated according to randomisation; and As treated (AT), based on actual treatment received. The trial was undertaken in six hospitals in India with high-quality ICU facilities. An online application serving as the electronic case report form was developed to enable screening, randomisation and collection of outcomes data. Results: Adherence to treatment per protocol was 95.1%. Among all 387 participants, 77 (19.9%) developed critical disease needing ICU admission. In all three primary outcome analyses, doxycycline was associated with a relative risk reduction (RRR) and absolute risk reduction (ARR): ITT 31.6% RRR, 7.4% ARR (P=0.063); PP 40.7% RRR, 9.6% ARR (P=0.017); AT 43.2% RRR, 10.8% ARR (P=0.007), with numbers needed to treat (NTT) of 13.4 (ITT), 10.4 (PP), and 9.3 (AT), respectively. Doxycycline was well tolerated with not a single patient stopping treatment due to adverse events. Conclusions: In hospitalized COVID-19 patients, doxycycline, a safe, inexpensive, and widely available antibiotic with anti-inflammatory properties, reduces the need for ICU admission when added to SoC.","type":"Research","database":"MedRxiv","created":"2022-02-02"},{"id":2581,"name":"Montelukast is a dual-purpose inhibitor of SARS-CoV-2 infection and virus-induced IL-6 expression identified by structure-based drug repurposing.","author":"Max Luedemann, Daniela Stadler, Cho-Chin Cheng, Ulrike Protzer, Percy A.Knolle, Sainitin Donakonda","doi":"10.1016\/j.csbj.2022.01.024","abstract":"Drug-repurposing has been instrumental to identify drugs preventing SARS-CoV-2 replication or attenuating the disease course of COVID-19. Here, we identify through structure-based drug-repurposing a dual-purpose inhibitor of SARS-CoV-2 infection and of IL-6 production by immune cells. We created a computational structure model of the receptor binding domain (RBD) of the SARS-CoV-2 spike 1 protein, and used this model for insilico screening against a library of 6171 molecularly defined binding-sites from drug molecules. Molecular dynamics simulation of candidate molecules with high RBD binding-scores in docking analysis predicted montelukast, an antagonist of the cysteinyl-leukotriene-receptor, to disturb the RBD structure, and infection experiments demonstrated inhibition of SARS-CoV-2 infection, although montelukast binding was outside the ACE2-binding site. Molecular dynamics simulation of SARS-CoV-2 variant RBDs correctly predicted interference of montelukast with infection by the beta but not the more infectious alpha variant. With distinct binding sites for RBD and the leukotriene receptor, montelukast also prevented SARS-CoV-2-induced IL-6 release from immune cells. The inhibition of SARS-CoV-2 infection through a molecule binding distal to the ACE-binding site of the RBD points towards an allosteric mechanism that is not conserved in the more infectious alpha and delta SARS-CoV-2 variants.","type":"Research","database":"PMC","created":"2022-01-28"},{"id":2580,"name":"Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants.","author":"Yin, JialingLi, ChengchengYe, ChunhongRuan, ZhihuiLiang, YicongLi, YongkuiWu, JianguoLuo, Zhen","doi":"10.1016\/j.csbj.2022.01.026","abstract":null,"type":"Review","database":"PMC","created":"2022-01-30"},{"id":2579,"name":"A Phase 2 Randomized, Double-Blind, Placebo-controlled Trial of Oral Camostat Mesylate for Early Treatment of COVID-19 Outpatients Showed Shorter Illness Course and Attenuation of Loss of Smell and Taste","author":" G. Chupp, A. Spichler-Moffarah, O. S. Sogaard, D. Esserman, J. Dziura, L. Danzig, R. Chaurasia, K. P. Patra, A. Salovey, A. Nunez, J. May, L. Astorino, A. Patel, S. Halene, J. Wang, P. Hui, P. Patel, J. Lu, F. Li, G. Gan, S. Parziale, L. Katsovich, G. Desir, J. M. Vinetz,","doi":"10.1101\/2022.01.28.22270035","abstract":"Importance: Early treatment of mild SARS-CoV-2 infection might lower the risk of clinical deterioration in COVID-19. Objective: To determine whether oral camostat mesylate would reduce upper respiratory SARS-CoV-2 viral load in newly diagnosed outpatients with mild COVID-19, and would lead to improvement in COVID-19 symptoms. Design: From June, 2020 to April, 2021, we conducted a randomized, double-blind, placebo-controlled phase 2 trial. Setting: Single site, academic medical center, outpatient setting in Connecticut, USA. Participants: Of 568 COVID-19 positive potential adult participants diagnosed within 3 days of study entry and assessed for eligibility, 70 were randomized and 498 were excluded (198 did not meet eligibility criteria, 37 were not interested, 265 were excluded for unknown or other reasons). The primary inclusion criteria were a positive SARS-CoV-2 nucleic acid amplification result in adults within 3 days of screening regardless of COVID-19 symptoms. Intervention: Treatment was 7 days of oral camostat mesylate, 200 mg po four times a day, or placebo. Main Outcomes and Measures: The primary outcome was reduction of 4-day log10 nasopharyngeal swab viral load by 0.5 log10 compared to placebo. The main prespecified secondary outcome was reduction in symptom scores as measured by a quantitative Likert scale instrument, Flu-PRO-Plus modified to measure changes in smell\/taste measured using FLU-PRO-Plus. Results: Participants receiving camostat had statistically significant lower quantitative symptom scores (FLU-Pro-Plus) at day 6, accelerated overall symptom resolution and notably improved taste\/smell, and fatigue beginning at onset of intervention in the camostat mesylate group compared to placebo. Intention-to-treat analysis demonstrated that camostat mesylate was not associated with a reduction in 4-day log10 NP viral load compared to placebo. Conclusions and relevance: The camostat group had more rapid resolution of COVID-19 symptoms and amelioration of the loss of taste and smell. Camostat compared to placebo was not associated with reduction in nasopharyngeal SARS-COV-2 viral load. Additional clinical trials are warranted to validate the role of camostat mesylate on SARS-CoV-2 infection in the treatment of mild COVID-19. Trial registration: Clinicaltrials.gov, NCT04353284 (04\/20\/20) (https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04353284?term=camostat+%2C+yale&amp;draw=2&amp;rank=1)","type":"Research","database":"MedRxiv","created":"2022-01-30"},{"id":2577,"name":"Defining the Substrate Envelope of SARS-CoV-2 Main Protease to Predict and Avoid Drug Resistance","author":" A. M. Shaqra, S. Zvornicanin, Q. Y. Huang, G. J. Lockbaum, M. Knapp, L. Tandeske, D. T. Barkan, J. Flynn, D. N. Bolon, S. Moquin, D. Dovala, N. Kurt Yilmaz, C. A. Schiffer,","doi":"10.1101\/2022.01.25.477757","abstract":"Coronaviruses, as exemplified by SARS-CoV-2, can evolve and spread rapidly to cause severe disease morbidity and mortality. Direct acting antivirals (DAAs) are highly effective in decreasing disease burden especially when they target essential viral enzymes, such as proteases and polymerases, as demonstrated in HIV-1 and HCV and most recently SARS-CoV-2. Optimization of these DAAs through iterative structure-based drug design has been shown to be critical. Particularly, the evolutionarily conserved molecular mechanisms underlying viral replication can be leveraged to develop robust antivirals against rapidly evolving viral targets. The main protease (Mpro) of SARS-CoV-2, which is evolutionarily constrained to recognize and cleave 11 specific sites to promote viral maturation, exemplifies one such target. In this study we define the substrate envelope of Mpro by determining the molecular basis of substrate recognition, through nine high-resolution cocrystal structures of SARS-CoV-2 Mpro with the viral cleavage sites. These structures enable identification of evolutionarily vulnerable sites beyond the substrate envelope that may be susceptible to drug resistance and compromise binding of the newly developed Mpro inhibitors.","type":"Research","database":"BioRxiv","created":"2022-01-26"},{"id":2574,"name":"A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus.","author":"William A Fischer, Joseph J Eron, Wayne Holman, Myron S Cohen, Lei Fang, Laura J Szewczyk, Timothy P Sheahan, Ralph Baric, Katie R Mollan, Cameron R Wolfe, Elizabeth R Duke, Masoud M Azizad, Katyna Borroto-Esoda, David A Wohl, Robert W Coombs, Amy James Loftis, Paul Alabanza, Felicia Lipansky, Wendy P Painter, ","doi":"10.1126\/scitranslmed.abl7430","abstract":"There is an urgent need for an effective, oral, direct-acting therapeutic to block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent progression to severe coronavirus disease 2019 (COVID-19). In a phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and symptom duration <7 days. Participants were randomized 1:1 to receive molnupiravir (200 mg) or placebo and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800-mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank <i>P<\/i> value = 0.013). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800-mg molnupiravir group compared with 16.7% of the placebo group at day 3 of treatment (<i>P<\/i> = 0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients (<i>P<\/i> = 0.034 and 0.027, respectively). Molnupiravir was well tolerated across all doses.","type":"Research","database":"PubMed","created":"2022-01-18"},{"id":2566,"name":"Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19.","author":"Wu, Can-rongYin, Wan-chaoJiang, YiXu, H. Eric","doi":"10.1038\/s41401-021-00851-w","abstract":"Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer\u2019s novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck\u2019s nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies.","type":"Review","database":"PMC","created":"2022-01-19"},{"id":2564,"name":"Interferon Control of Human Coronavirus Infection and Viral Evasion: Mechanistic Insights and Implications for Antiviral Drug and Vaccine Development.","author":"Zhao, XuesenChen, DanyingLi, XinglinGriffith, LaurenChang, JinhongAn, PingGuo, Ju-Tao","doi":"10.1016\/j.jmb.2021.167438","abstract":"Recognition of viral infections by various pattern recognition receptors (PRRs) activates an inflammatory cytokine response that inhibits viral replication and orchestrates the activation of adaptive immune responses to control the viral infection. The broadly active innate immune response puts a strong selective pressure on viruses and drives the selection of variants with increased capabilities to subvert the induction and function of antiviral cytokines. This revolutionary process dynamically shapes the host ranges, cell tropism and pathogenesis of viruses. Recent studies on the innate immune responses to the infection of human coronaviruses (HCoV), particularly SARS-CoV-2, revealed that HCoV infections can be sensed by endosomal toll-like receptors and\/or cytoplasmic RIG-I-like receptors in various cell types. However, the profiles of inflammatory cytokines and transcriptome response induced by a specific HCoV are usually cell type specific and determined by the virus-specific mechanisms of subverting the induction and function of interferons and inflammatory cytokines as well as the genetic trait of the host genes of innate immune pathways. We review herein the recent literatures on the innate immune responses and their roles in the pathogenesis of HCoV infections with emphasis on the pathobiological roles and therapeutic effects of type I interferons in HCoV infections and their antiviral mechanisms. The knowledge on the mechanism of innate immune control of HCoV infections and viral evasions should facilitate the development of therapeutics for induction of immune resolution of HCoV infections and vaccines for efficient control of COVID-19 pandemics and other HCoV infections.","type":"Review","database":"PMC","created":"2022-01-02"},{"id":2559,"name":"COVID MED - An Early Pandemic Trial of Losartan for Hospitalized COVID-19 Patients","author":" D. Freilich, J. Victory, P. Jenkins, J. Wheeler, G. M. Vail, E. Riesenfeld, P. Cross, C. Gilmore, M. Huckabone, A. Schworm, U. Boregowda, F. Deshmukh, Y. Choi, A. Kahn, A. Gadomski,","doi":"10.1101\/2022.01.12.22269095","abstract":"Background ACEi\/ARB medications have been hypothesized to have potential benefit in COVID-19. Despite concern for increased ACE-2 expression in some animal models, preclinical and observational-retrospective and uncontrolled trials suggested possible benefit. Two RCTs of the ARB losartan from University of Minnesota showed no benefit yet safety signals for losartan in outpatient and hospitalized COVID-19 patients. COVID MED, started early in the pandemic, also assessed losartan in a RCT in hospitalized patients with COVID-19. Methods COVID MED was quadruple-blinded, placebo-controlled, multicenter randomized clinical trial (RCT). Hospitalized COVID-19 patients were randomized to receive standard care and hydroxychloroquine, lopinavir\/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir\/ritonavir arms were discontinued after RCTs showed no benefit. We report data from the losartan arm compared to combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint was the NCOSS slope of change. Slow enrollment prompted early stopping. Results Of 432 screened patients, 14 were enrolled (3.5%), 9 received losartan and 5 combined control (lopinavir\/ritonavir [N=2], placebo [N=3]); 1 hydroxychloroquine arm patient was excluded. Most baseline parameters were balanced. Treatment with losartan was not associated with a difference in NCOSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan. Conclusions In this small blinded RCT in hospitalized COVID-19 patients, losartan did not improve outcome vs. control comparisons and was associated with adverse safety signals.","type":"Research","database":"MedRxiv","created":"2022-01-14"},{"id":2516,"name":"A Review on Repurposed Drugs and Vaccine Trials for Combating SARS CoV-2.","author":"Nikita Khanna, Sandip V Pawar, Anil Kumar, ","doi":"10.2174\/2589977513666210315094752","abstract":"The novel coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019 and then spread worldwide rapidly. The records from World Health Organisation (WHO), Centres of Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) backup the fact that no medications have proven to be completely effective for prevention or treatment of SARS-CoV-2. The clinical trials are underway for many repurposed, investigational drugs and vaccine candidates. BioNTech and Pfizer Inc, Moderna, Gamaleya institute and University of Oxford (collaboration with AstraZeneca) announced positive results in the Phase 3 interim analyses of vaccine trials in November 2020. Twelve countries have approved Pfizer- BioNTech COVID-19 vaccine for emergency use, as of December 2020.","type":"Review","database":"PubMed","created":null},{"id":2508,"name":"An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.","author":"Dro\u017cd\u017cal, SylwesterRosik, JakubLechowicz, KacperMachaj, FilipSzostak, BartoszPrzybyci\u0144ski, Jaros\u0142awLorzadeh, ShahrokhKotfis, KatarzynaGhavami, Saeid\u0141os, Marek J.","doi":"10.1016\/j.drup.2021.100794","abstract":"The COVID-19 pandemic is one of the greatest threats to human health in the 21st century with more than 257 million cases and over 5.17 million deaths reported worldwide (as of November 23, 2021. Various agents were initially proclaimed to be effective against SARS-CoV-2, the etiological agent of COVID-19. Hydroxychloroquine, lopinavir\/ritonavir, and ribavirin are all examples of therapeutic agents, whose efficacy against COVID-19 was later disproved. Meanwhile, concentrated efforts of researchers and clinicians worldwide have led to the identification of novel therapeutic options to control the disease including PAXLOVID\u2122 (PF-07321332). Although COVID-19 cases are currently treated using a comprehensive approach of anticoagulants, oxygen, and antibiotics, the novel Pfizer agent PAXLOVID\u2122 (PF-07321332), an investigational COVID-19 oral antiviral candidate, significantly reduced hospitalization time and death rates, based on an interim analysis of the phase 2\/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness. The scheduled interim analysis demonstrated an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint). However, there still exists a great need for the development of additional treatments, as the recommended therapeutic options are insufficient in many cases. Thus far, mRNA and vector vaccines appear to be the most effective modalities to control the pandemic. In the current review, we provide an update on the progress that has been made since April 2020 in clinical trials concerning the effectiveness of therapies available to combat COVID-19. We focus on currently recommended therapeutic agents, including steroids, various monoclonal antibodies, remdesivir, baricitinib, anticoagulants and PAXLOVID\u2122 summarizing the latest original studies and meta-analyses. Moreover, we aim to discuss other currently and previously studied agents targeting COVID-19 that either show no or only limited therapeutic activity. The results of recent studies report that hydroxychloroquine and convalescent plasma demonstrate no efficacy against SARS-CoV-2 infection. Lastly, we summarize the studies on various drugs with incoherent or insufficient data concerning their effectiveness, such as amantadine, ivermectin, or niclosamide.","type":"Review","database":"PMC","created":"2021-12-08"},{"id":2494,"name":"Drug-based therapeutic strategies for COVID-19-infected patients and their challenges.","author":"Zarkesh, KhaterehEntezar-Almahdi, ElahehGhasemiyeh, ParisaAkbarian, MohsenBahmani, MarziehRoudaki, ShahrzadFazlinejad, RahilMohammadi-Samani, SolimanFirouzabadi, NegarHosseini, MajidFarjadian, Fatemeh","doi":"10.2217\/fmb-2021-0116","abstract":"Emerging epidemic-prone diseases have introduced numerous health and economic challenges in recent years. Given current knowledge of COVID-19, herd immunity through vaccines alone is unlikely. In addition, vaccination of the global population\u00a0is an ongoing challenge. Besides, the questions regarding the prevalence and the timing of immunization are still under investigation. Therefore, medical treatment remains essential in the management of COVID-19. Herein, recent advances from beginning observations of COVID-19 outbreak to an understanding of the essential factors contributing to the spread and transmission of COVID-19 and its treatment are reviewed. Furthermore, an in-depth discussion on the epidemiological aspects, clinical symptoms and most efficient medical treatment strategies to mitigate the mortality and spread rates of COVID-19 is presented.","type":"Review","database":"PMC","created":"2021-10-11"},{"id":2493,"name":"Coronavirus Disease (COVID-19) Control between Drug Repurposing and Vaccination: A Comprehensive Overview.","author":"Al-Karmalawy, Ahmed A.Soltane, RayaAbo Elmaaty, AymanTantawy, Mohamed A.Antar, Samar A.Yahya, GalalChrouda, AmaniPashameah, Rami AdelMustafa, MuhamadAbu Mraheil, MobarakMostafa, Ahmed","doi":"10.3390\/vaccines9111317","abstract":"Respiratory viruses represent a major public health concern, as they are highly mutated, resulting in new strains emerging with high pathogenicity. Currently, the world is suffering from the newly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus is the cause of coronavirus disease 2019 (COVID-19), a mild-to-severe respiratory tract infection with frequent ability to give rise to fatal pneumonia in humans. The overwhelming outbreak of SARS-CoV-2 continues to unfold all over the world, urging scientists to put an end to this global pandemic through biological and pharmaceutical interventions. Currently, there is no specific treatment option that is capable of COVID-19 pandemic eradication, so several repurposed drugs and newly conditionally approved vaccines are in use and heavily applied to control the COVID-19 pandemic. The emergence of new variants of the virus that partially or totally escape from the immune response elicited by the approved vaccines requires continuous monitoring of the emerging variants to update the content of the developed vaccines or modify them totally to match the new variants. Herein, we discuss the potential therapeutic and prophylactic interventions including repurposed drugs and the newly developed\/approved vaccines, highlighting the impact of virus evolution on the immune evasion of the virus from currently licensed vaccines for COVID-19.","type":"Review","database":"PMC","created":"2021-11-11"},{"id":2492,"name":"Structures and functions of coronavirus replication\u2013transcription complexes and their relevance for SARS-CoV-2 drug design.","author":"Malone, BrandonUrakova, NadyaSnijder, Eric J.Campbell, Elizabeth A.","doi":"10.1038\/s41580-021-00432-z","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to cause massive global upheaval. Coronaviruses are positive-strand RNA viruses with an unusually large genome of ~30\u2009kb. They express an RNA-dependent RNA polymerase and a cohort of other replication enzymes and supporting factors to transcribe and replicate their genomes. The proteins performing these essential processes are prime antiviral drug targets, but drug discovery is hindered by our incomplete understanding of coronavirus RNA synthesis and processing. In infected cells, the RNA-dependent RNA polymerase must coordinate with other viral and host factors to produce both viral mRNAs and new genomes. Recent research aiming to decipher and contextualize the structures, functions and interplay of the subunits of the SARS-CoV-2 replication and transcription complex proteins has burgeoned. In this Review, we discuss recent advancements in our understanding of the molecular basis and complexity of the coronavirus RNA-synthesizing machinery. Specifically, we outline the mechanisms and regulation of RNA translation, replication and transcription. We also discuss the composition of the replication and transcription complexes and their suitability as targets for antiviral therapy.","type":"Review","database":"PMC","created":"2021-11-24"},{"id":2490,"name":"Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial","author":" M. Holubar, A. K. Subramanian, N. Purington, H. Hedlin, B. Bunning, K. Walter, H. Bonilla, A. Boumis, M. Chen, K. Clinton, L. Dewhurst, C. Epstein, P. Jagannathan, R. Kaszynski, L. Panu, J. Parsonnet, E. Ponder, O. Quintero, E. Sefton, U. Singh, L. Soberanis, H. Truong, J. Andrews, M. Desai, C. Khosla, Y. Maldonado,","doi":"10.1101\/2021.11.22.21266690","abstract":"Background: Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries. Methods: We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV2 deep sequencing, we assessed the impact of favipiravir on mutagenesis. Results: From July 8, 2020 to March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 - 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 - 1.29; sustained: HR 0.87, 95% CI 0.52 - 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment. Conclusions: Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.","type":"Research","database":"MedRxiv","created":"2021-11-23"},{"id":2487,"name":"In silico validation of anti-viral drugs obtained from marine sources as a potential target against SARS-CoV-2 Mpro.","author":"Ghosh, SrijitDas, SrijitaAhmad, IqrarPatel, Harun","doi":"10.1016\/j.jics.2021.100272","abstract":"COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has threatened the whole world affecting almost 243 million people globally. Originating from China, it has now spread worldwide with USA and India being the two most affected countries which emphasizes the immense potential of the coronaviruses to cause severity in the human population. This study validates the efficacy of some marine antiviral agents to target the viral main protease (Mpro) of SARS-CoV-2 by in silico studies. A total of 14 marine-derived antiviral agents were screened from several databases including PubChem and DrugBank and docked against the crystallised 3D structure of SARS-CoV-2 Mpro. MD simulation of the top two ligands was carried out for 100 ns to validate the protein-ligand stability. Later, their physicochemical, pharmacokinetics, and drug-likeness properties were evaluated and toxicity prediction was performed using eMOLTOX webtool. We found that all the 14 compounds are acting as a good target for Mpro. Among them, avarol and AcDa-1 procured the best docking results with the estimated docking score of \u22128.05 and \u22127.74\u00a0\u200bkcal\/mol respectively. MD simulation revealed good conformational stability. The docked conformation was visualised and subsequent ligand-amino acid interactions were analysed. Avarol revealed good pharmacokinetic properties with oral bioavailability. The overall finding suggested that these marine compounds may have the potential to be used for the treatment of COVID-19 to tackle this pandemic.","type":"Research","database":"PMC","created":"2021-11-18"},{"id":2485,"name":"Combined deep learning and molecular docking simulations approach identifies potentially effective FDA approved drugs for repurposing against SARS-CoV-2.","author":"Anwaar, Muhammad U.Adnan, FarjadAbro, AsmaKhan, Rayyan A.Rehman, Asad U.Osama, MuhammadRainville, ChristopherKumar, SureshSterner, DavidJaved, SaadJamal, Syed B.Baig, AhmadullahShabbir, Muhammad R.Ahsan, WasehButt, Tauseef R.Assir, Muhammad Z.","doi":"10.1016\/j.compbiomed.2021.105049","abstract":"The ongoing pandemic of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health. Drug repurposing is a time-efficient approach to finding effective drugs against SARS-CoV-2 in this emergency. Here, we present a robust experimental design combining deep learning with molecular docking experiments to identify the most promising candidates from the list of FDA-approved drugs that can be repurposed to treat COVID-19. We have employed a deep learning-based Drug Target Interaction (DTI) model, called DeepDTA, with few improvements to predict drug-protein binding affinities, represented as KIBA scores, for 2440 FDA-approved and 8168 investigational drugs against 24 SARS-CoV-2 viral proteins. FDA-approved drugs with the highest KIBA scores were selected for molecular docking simulations. We ran around 50,000 docking simulations for 168 selected drugs against 285 total predicted and\/or experimentally proven active sites of all 24 SARS-CoV-2 viral proteins. A list of 49 most promising FDA-approved drugs with the best consensus KIBA scores and binding affinity values against selected SARS-CoV-2 viral proteins was generated. Most importantly, 16 drugs including anidulafungin, velpatasvir, glecaprevir, rifapentine, flavin adenine dinucleotide (FAD), terlipressin, and selinexor demonstrated the highest predicted inhibitory potential against key SARS-CoV-2 viral proteins. We further measured the inhibitory activity of 5 compounds (rifapentine, velpatasvir, glecaprevir, anidulafungin, and FAD disodium) on SARS-CoV-2 PLpro using Ubiquitin-Rhodamine 110 Gly fluorescent intensity assay. The highest inhibition of PLpro activity was seen with rifapentine (IC50: 15.18\u00a0\u03bcM) and FAD disodium (IC50: 12.39\u00a0\u03bcM), the drugs with high predicted KIBA scores and binding affinities.","type":"Research","database":"PMC","created":"2021-11-19"},{"id":2479,"name":"An update comprehensive review on the status of COVID-19: vaccines, drugs, variants and neurological symptoms.","author":"\u00d6ZKAN OKTAY, EbruTUNCAY, SalihKAMAN, Tu\u011fbaKARASAKAL, \u00d6mer Faruk\u00d6ZCAN, \u00d6znur \u00d6zgeSOYLAMI\u015e, Tu\u011f\u00e7eKARAHAN, MesutKONUK, Muhsin","doi":"10.3906\/biy-2106-23","abstract":"Various recently reported mutant variants, candidate and urgently approved current vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many current situations with severe neurological damage and symptoms as well as respiratory tract disorders have begun to be reported. In particular, drug, vaccine, and neutralizing monoclonal antibodies (mAbs) have been developed and are currently being evaluated in clinical trials. Here, we review lessons learned from the use of novel mutant variants of the COVID-19 virus, immunization, new drug solutions, and antibody therapies for infections. Next, we focus on the B 1.1.7, B 1.351, P.1, and B.1.617 lineages or variants of concern that have been reported worldwide, the new manifestations of neurological manifestations, the current therapeutic drug targets for its treatment, vaccine candidates and their efficacy, implantation of convalescent plasma, and neutralization of mAbs. We review specific clinical questions, including many emerging neurological effects and respiratory tract injuries, as well as new potential biomarkers, new studies in addition to known therapeutics, and chronic diseases of vaccines that have received immediate approval. To answer these questions, further understanding of the burden kinetics of COVID-19 and its correlation with neurological clinical outcomes, endogenous antibody responses to vaccines, pharmacokinetics of neutralizing mAbs, and action against emerging viral mutant variants is needed.","type":"Research","database":"PMC","created":"2021-08-29"},{"id":2475,"name":"Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations","author":"Bilal Ahmad, Maria Batool, Qurat Ul Ain, Moon Suk Kim, Sangdun Choi","doi":"10.3390\/ijms22179124","abstract":"The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, \u03b1-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, \u03b1-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-\u03b1-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and \u03b1-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of \u03b1-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.","type":"Research","database":"PubMed","created":"2021-11-14"},{"id":2474,"name":"Molnupiravir in COVID-19: A systematic review of literaturef","author":"Awadhesh Kumar Singh , Akriti Singh , Ritu Singh , Anoop Misra","doi":"10.1016\/j.dsx.2021.102329","abstract":"Background and aims: Molnupiravir is a newer oral antiviral drug that has recently been tested in COVID-19. We aim to conduct a systematic review of literature to find out the efficacy and safety of molnupiravir in patients with COVID-19.\r\n\r\nMethods: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar from inception until October 15, 2021, using MeSH keywords. Ongoing trials of molnupiravir in COVID-19 were additionally searched from the ClinicalTrials.Gov and ctri.nic.in\/Clinicaltrials. We retrieved all the available granular details of phase 1 to 3 studies of molnupiravir in COVID-19. Subsequently we reviewed the results narratively.\r\n\r\nResults: Two phase 1 double-blind, randomized, placebo-controlled (DBRPC) studies of molnupiravir showed that 1600 mg daily dose is safe and tolerable, without any serious adverse events up to 5.5 days. One phase 2 DBPRC study found significantly lower time to clearance (RNA negativity) with molnupiravir 800 mg twice daily compared to the placebo (log-rank p value = 0.013) in mild to moderate COVID-19. Interim report of one phase 3 DBRPC study in non-hospitalized COVID-19 found a significant reduction in the risk of hospital admission or death by 50% (p = 0.0012). However, no significant benefit was observed with molnupiravir in the later stage of moderate to severe COVID-19.\r\n\r\nConclusion: Molnupiravir is first oral antiviral drug to demonstrate a significant benefit in reducing hospitalization or death in mild COVID-19 and could be an important weapon in the battle against SARS-CoV-2. However, its role in moderate to severe COVID-19 is questionable and more studies are needed.","type":"Review","database":"PubMed","created":"2021-11-14"},{"id":2472,"name":"Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases","author":" T. Linden, F. Hanses, D. Domingo-Fernandez, L. N. DeLong, A. T. Kodamullil, J. Schneider, M. J. G. T. Vehreschild, J. Lanznaster, M. M. Ruethrich, S. Borgmann, M. Hower, K. Wille, T. Feldt, S. Rieg, B. Hertenstein, C. Wyen, C. Roemmele, J. J. Vehreschild, C. E. M. Jakob, M. Stecher, M. Kuzikov, A. Zaliani, H. Froehlich, LEOSS study group,","doi":"10.1101\/2021.11.11.21266048","abstract":"Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimers Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.","type":"Research","database":"MedRxiv","created":"2021-11-11"},{"id":2470,"name":"Drug repurposing against SARS-CoV-1, SARS-CoV-2\u00a0and MERS-CoV.","author":"Aherfi, SarahPradines, BrunoDevaux, ChristianHonore, St\u00e9phaneColson, PhilippeScola, Bernard LaRaoult, Didier","doi":"10.2217\/fmb-2021-0019","abstract":"Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy\u00a0because of\u00a0the reduced time for approval by international medicines agencies, the low cost of development\u00a0and the well-known toxicity profile of such drugs. Herein, we aim\u00a0to review drugs with\u00a0in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of\u00a0nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine\u00a0and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.","type":"Review","database":"PMC","created":"2021-10-07"},{"id":2468,"name":"Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial.","author":" S. Shenoy, S. Munjal, S. Al Youha, M. Alghounaim, S. Almazeedi, Y. Alshamali, R. H. Kaszynski, S. K. Al-Sabah, Kuwait Clinical Trial Group,","doi":"10.1101\/2021.11.08.21265884","abstract":"Aim: To assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19). Methods: In this randomized, double-blind, multicenter, phase 3 trial, adults (21 80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS CoV 2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia. Results: In total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240\/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) (p=0.94)]. Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) (p=0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) (p=0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) (p=0.38)] than higher NEWS-2 clinical risk subgroup. Treatment emergent adverse event (TEAEs) were experienced by 62\/334 (19%) patients [35\/168 (21%) patients in FPV and 27\/166 (16%) in placebo group]. Hyperuricaemia\/increased blood uric acid was reported in 9 (3%)\/2 (1%) patients [8 (5%)\/1(1%) patients in FPV and 1 (1%)\/1(1%) in placebo group] ,which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group. Conclusion: The trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.","type":"Research","database":"MedRxiv","created":"2021-11-08"},{"id":2464,"name":"Effect of the Neutralizing SARS-CoV-2 Antibody Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial","author":" A. Gupta, Y. Gonzalez-Rojas, E. Juarez, M. Crespo, J. Moya, D. Falci, E. Sarkis, J. Solis, H. Zheng, N. Scott, A. L. Cathcart, S. Parra, J. E. Sager, D. J. Austin, A. Peppercorn, E. Alexander, W. W. Yeh, C. Brinson, M. Aldinger, A. E. Shapiro,","doi":"10.1101\/2021.11.03.21265533","abstract":"Importance: Older patients and those with underlying comorbidities infected with SARS-CoV-2 may be at increased risk of hospitalization and death from COVID-19. Sotrovimab is a neutralizing antibody designed for treatment of high-risk patients to prevent COVID-19 progression. Objective: To evaluate the efficacy and safety of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease. Design: Randomized, double-blind, multicenter, placebo-controlled, phase 3 study. Setting: 57 centers in 5 countries. Participants: Nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for disease progression. Intervention: Patients were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with COVID-19 progression, defined as all-cause hospitalization longer than 24 hours for acute illness management or death through day 29. Key secondary outcomes included the proportion of patients with COVID-19 progression, defined as emergency room visit, hospitalization of any duration, or death, and proportion of patients developing severe\/critical respiratory COVID-19 requiring supplemental oxygen. Results: Among 1057 patients randomized (sotrovimab, 528; placebo, 529), all-cause hospitalization longer than 24 hours or death was significantly reduced with sotrovimab (6\/528 [1%]) vs placebo (30\/529 [6%]) by 79% (95% CI, 50% to 91%; P<.001). Secondary outcome results further demonstrated the effect of sotrovimab in reducing emergency room visits, hospitalization of any duration, or death, which was reduced by 66% (95% CI, 37% to 81%; P<.001), and severe\/critical respiratory COVID-19, which was reduced by 74% (95% CI, 41% to 88%; P=.002). No patients receiving sotrovimab required high-flow oxygen, oxygen via nonrebreather mask, or mechanical ventilation compared with 14 patients receiving placebo. The proportion of patients reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no safety concerns were identified. Conclusions and Relevance: Among nonhospitalized patients with mild to moderate COVID-19, a single 500-mg intravenous dose of sotrovimab prevented progression of COVID-19, with a reduction in hospitalization and need for supplemental oxygen. Sotrovimab is a well-tolerated, effective treatment option for patients at high risk for severe morbidity and mortality from COVID-19.","type":"Research","database":"MedRxiv","created":"2021-11-07"},{"id":2463,"name":"Structural basis of main proteases of coronavirus bound to drug candidate PF-07321332","author":" J. Li, C. Lin, X. Zhou, F. Zhong, P. Zeng, H. Jiang, Y. Yang, P. McCormick, Y. Fu, J. Zhang,","doi":"10.1101\/2021.11.05.467529","abstract":"The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genus of coronaviruses is the substrate binding site of the main protease (Mpro or 3CLpro), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332 developed by Pfizer is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here we report three crystal structures of main protease of SARS-CoV-2, SARS-CoV and MERS-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of main protease harbors multiple inhibitor binding sites, where PF-07321332 occupies subsites S1, S2 and S4 and appears more restricted compared with other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of main proteases from different coronaviruses. Given the importance of main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals.","type":"Research","database":"BioRxiv","created":"2021-11-07"},{"id":2457,"name":"Brilacidin, a COVID-19 Drug Candidate, demonstrates broad-spectrum antiviral activity against human coronaviruses OC43, 229E and NL63 through targeting both the virus and the host cell","author":" Y. Hu, H. Jo, W. DeGrado, J. Wang,","doi":"10.1101\/2021.11.04.467344","abstract":"Brilacidin, a mimetic of host defense peptides (HDPs), is currently in phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against SARS-CoV-2 by inactivating the virus. In this work, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, a HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.","type":"Research","database":"BioRxiv","created":"2021-11-04"},{"id":2456,"name":"Clinical features and mechanistic insights into drug repurposing for combating COVID-19.","author":"Asrani, PurvaTiwari, KeshavEapen, Mathew SujiMcAlinden, Kielan DarcyHaug, GregJohansen, Matt DHansbro, Philip MFlanagan, Katie LHassan, Md. ImtaiyazSohal, Sukhwinder Singh","doi":"10.1016\/j.biocel.2021.106114","abstract":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from Wuhan in China before it spread to the entire globe. It causes coronavirus disease of 2019 (COVID-19) where mostly individuals present mild symptoms, some remain asymptomatic and some show severe lung inflammation and pneumonia in the host through the induction of a marked inflammatory \u2018cytokine storm\u2019. New and efficacious vaccines have been developed and put into clinical practice in record time, however, there is a still a need for effective treatments for those who are not vaccinated or remain susceptible to emerging SARS-CoV-2 variant strains. Despite this, effective therapeutic interventions against COVID-19 remain elusive. Here we review potential drugs for COVID-19 classified on the basis of their mode of action. The mechanisms of action of each are discussed in detail to highlight the therapeutic targets that may help in reducing the global pandemic. The review was done up to July 2021 and the data was assessed through the official websites of WHO and CDC for collecting the information on the clinical trials. Moreover, the recent research papers were also assessed for the relevant data. The search was made based on keywords like Coronavirus, SARS-C0V-2, drugs (specific name of the drugs), COVID-19, clinical efficiency, safety profile, side-effects etc.This review outlines potential areas for future research into COVID-19 treatment strategies.","type":"Review","database":"PMC","created":"2021-11-04"},{"id":2455,"name":"Current status of structure-based drug repurposing against COVID-19 by targeting SARS-CoV-2 proteins.","author":"Hijikata, AtsushiShionyu, ClaraNakae, SetsuShionyu, MasafumiOta, MotonoriKanaya, ShigehikoShirai, Tsuyoshi","doi":"10.2142\/biophysico.bppb-v18.025","abstract":"More than one and half years have passed, as of August 2021, since the COVID-19 caused by the novel coronavirus named SARS-CoV-2 emerged in 2019. While the recent success of vaccine developments likely reduces the severe cases, there is still a strong requirement of safety and effective therapeutic drugs for overcoming the unprecedented situation. Here we review the recent progress and the status of the drug discovery against COVID-19 with emphasizing a structure-based perspective. Structural data regarding the SARS-CoV-2 proteome has been rapidly accumulated in the Protein Data Bank, and up to 68% of the total amino acid residues encoded in the genome were covered by the structural data. Despite a global effort of in silico and in vitro screenings for drug repurposing, there is only a limited number of drugs had been successfully authorized by drug regulation organizations. Although many approved drugs and natural compounds, which exhibited antiviral activity in vitro, were considered potential drugs against COVID-19, a further multidisciplinary investigation is required for understanding the mechanisms underlying the antiviral effects of the drugs.","type":"Review","database":"PMC","created":"2021-10-04"},{"id":2450,"name":"Comparison of viral RNA\u2013host protein interactomes across pathogenic RNA viruses informs rapid antiviral drug discovery for SARS-CoV-2.","author":"Zhang, ShaojunHuang, WenzeRen, LiliJu, XiaohuiGong, MingliRao, JianSun, LeiLi, PanDing, QiangWang, JianweiZhang, Qiangfeng Cliff","doi":"10.1038\/s41422-021-00581-y","abstract":"In contrast to the extensive research about viral protein\u2013host protein interactions that has revealed major insights about how RNA viruses engage with host cells during infection, few studies have examined interactions between host factors and viral RNAs (vRNAs). Here, we profiled vRNA\u2013host protein interactomes for three RNA virus pathogens (SARS-CoV-2, Zika, and Ebola viruses) using ChIRP-MS. Comparative interactome analyses discovered both common and virus-specific host responses and vRNA-associated proteins that variously promote or restrict viral infection. In particular, SARS-CoV-2 binds and hijacks the host factor IGF2BP1 to stabilize vRNA and augment viral translation. Our interactome-informed drug repurposing efforts identified several FDA-approved drugs (e.g., Cepharanthine) as broad-spectrum antivirals in cells and hACE2 transgenic mice. A co-treatment comprising Cepharanthine and Trifluoperazine was highly potent against the newly emerged SARS-CoV-2 B.1.351 variant. Thus, our study illustrates the scientific and medical discovery utility of adopting a comparative vRNA\u2013host protein interactome perspective.","type":"Research","database":"PMC","created":"2021-11-03"},{"id":2438,"name":"Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2","author":" T. Hussain, M. Afsar, R. Narayan, M. N. Akhtar, H. Rahil, S. Eswarappa, S. Tripathi,","doi":"10.1101\/2021.11.02.466951","abstract":"The SARS-Cov-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARSCov-2 bind in the mRNA entry channel of the 40S ribosomal subunit and block the entry of mRNAs thereby shutting down host protein synthesis. Nsp1 suppresses the host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics. In this study, we have in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter and find that montelukast sodium hydrate binds to Nsp1-C-ter with a binding affinity (KD) of 10.8{+\/-}0.2 M in vitro and forms a stable complex with it in simulation runs with a binding energy of - 76.71{+\/-}8.95 kJ\/mol. The drug also rescues the inhibitory effect of Nsp1 in host protein synthesis as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, montelukast sodium hydrate demonstrates antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells. We therefore propose montelukast sodium hydrate may help in combatting SARS-CoV-2 infection.","type":"Research","database":"BioRxiv","created":"2021-11-02"},{"id":2406,"name":"Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational and In Vitro Study.","author":"Banerjee, SouvikYadav, ShaliniBanerjee, SouravFakayode, Sayo O.Parvathareddy, JyothiReichard, WalterSurendranathan, SurekhaMahmud, FoyezWhatcott, RyanThammathong, JoshuaMeibohm, BerndMiller, Duane D.Jonsson, Colleen B.Dubey, Kshatresh Dutta","doi":"10.1021\/acs.jcim.1c00524","abstract":"COVID-19, an acute viral pneumonia, has emerged as a devastating pandemic. Drug repurposing allows researchers to find different indications of FDA-approved or investigational drugs. In this current study, a sequence of pharmacophore and molecular modeling-based screening against COVID-19 Mpro (PDB: 6LU7) suggested a subset of drugs, from the Drug Bank database, which may have antiviral activity. A total of 44 out of 8823 of the most promising virtual hits from the Drug Bank were subjected to molecular dynamics simulation experiments to explore the strength of their interactions with the SARS-CoV-2 Mpro active site. MD findings point toward three drugs (DB04020, DB12411, and DB11779) with very low relative free energies for SARS-CoV-2 Mpro with interactions at His41 and Met49. MD simulations identified an additional interaction with Glu166, which enhanced the binding affinity significantly. Therefore, Glu166 could be an interesting target for structure-based drug design. Quantitative structural\u2013activity relationship analysis was performed on the 44 most promising hits from molecular docking-based virtual screening. Partial least square regression accurately predicted the values of independent drug candidates\u2019 binding energy with impressively high accuracy. Finally, the EC50 and CC50 of 10 drug candidates were measured against SARS-CoV-2 in cell culture. Nilotinib and bemcentinib had EC50 values of 2.6 and 1.1 \u03bcM, respectively. In summary, the results of our computer-aided drug design provide a roadmap for rational drug design of Mpro inhibitors and the discovery of certified medications as COVID-19 antiviral therapeutics.","type":"Research","database":"PMC","created":"2021-10-19"},{"id":2405,"name":"Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern.","author":"Carter-Timofte, Madalina ElenaArulanandam, RozanneKurmasheva, NaziiaFu, KathyLaroche, Genevi\u00e8veTaha, Zaidvan der Horst, DemiCassin, Lenavan der Sluis, Ren\u00e9e M.Palermo, EnricoDi Carlo, DanieleJacobs, DavidMaznyi, GlibAzad, TahaSingaravelu, RagunathRen, FanghuiHansen, Anne LouiseIdorn, ManjaHolm, Christian K.Jakobsen, Martin R.van Grevenynghe, JulienHiscott, JohnPaludan, S\u00f8ren R.Bell, John C.Seguin, JeanSabourin, Luc A.C\u00f4t\u00e9, MarcelineDiallo, Jean-SimonAlain, TommyOlag","doi":"10.1021\/acsinfecdis.1c00278","abstract":"The antimicrobial medication malarone (atovaquone\/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone\/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.","type":"Research","database":"PMC","created":"2021-10-17"},{"id":2390,"name":"Darunavir Ethanolate: Repurposing an Anti-HIV Drug in COVID-19 Treatment.","author":"Chavda, Vivek P.Gajjar, NormiShah, NiravDave, Divyang J.","doi":"10.1016\/j.ejmcr.2021.100013","abstract":"Antivirals already on the market and expertise gained from the SARS and MERS outbreaks are gaining momentum as the most effective way to combat the coronavirus outbreak. SARS-CoV-2 has caused considerable mortality due to respiratory failure, highlighting the immediate need for successful therapies as well as the long-term need for antivirals to combat potential emergent coronaviruses. There are constant viral mutations are being observed due to which world is experiencing different waves of SARS-CoV-2. If our understanding of the virology and clinical presentation of COVID-19 grows, so does the pool of possible pharmacological targets. In COVID-19, the difficulties of proper analysis of current pre-clinical\/clinical data as well as the creation of new evidence concerning drug repurposing will be crucial. The current manuscript aims to evaluate the repurposing of an anti-HIV drug Darunavir Ethanolate in COVID-19 treatment with in silico study and we discuss the therapeutic progress of Darunavir Etanolate, to prevent SARS-CoV-2 replication, which supports its clinical assessment for COVID-19 therapy.","type":"Research","database":"PMC","created":"2021-10-21"},{"id":2363,"name":"Baricitinib plus Standard of Care for Hospitalised Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial.","author":" E. W. Ely, A. V. Ramanan, C. E. Kartman, S. de Bono, R. Liao, M. L. B. Piruzeli, J. D. Goldman, J. F. K. Saraiva, S. Chakladar, V. C. Marconi,","doi":"10.1101\/2021.10.11.21263897","abstract":"Background The oral, selective Janus kinase (JAK)1\/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).\r\n\r\nMethods COV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection (ClinicalTrials.gov NCT04421027). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV\/ECMO were randomly assigned 1:1 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.\r\n\r\nFindings SOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39\u00b72% vs 58\u00b70%; hazard ratio [HR]=0\u00b754 [95%CI 0\u00b731\u20130\u00b796]; p=0\u00b7030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45\u00b71% vs 62\u00b70%; HR=0\u00b756 [95%CI 0\u00b733\u20130\u00b797]; p=0\u00b7027).\r\n\r\nBaricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23\u00b77 vs 26\u00b71 days, p=0\u00b7050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms.\r\n\r\nInterpretation In critically ill patients with COVID-19 already receiving IMV\/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0\u00b756, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV-BARRIER study population.","type":"Research","database":"MedRxiv","created":"2021-10-11"},{"id":2360,"name":"Rilpivirine inhibits SARS-CoV-2 protein targets: A potential multi-target drug.","author":"Fuad Ameen, Estari Mamidala, Rakesh Davella, Shravan Vallala, ","doi":"10.1016\/j.jiph.2021.07.012","abstract":"Background\r\nCOVID-19 disease caused by SARS-CoV-2 is lacking efficient medication although certain medications are used to relief its symptoms.\r\n\r\nObjectives\r\nWe tested an FDA-approved antiviral medication namely rilpivirine to find a drug against SARS-CoV-2.\r\n\r\nMethods\r\nThe inhibition of rilpivirine against multiple SARS-CoV-2 therapeutic targets was studied using in silico method. The binding attraction of the protein-ligand complexes were calculated using molecular docking analysis.\r\n\r\nResults\r\nDocking rilpivirine with main protease (Mpro), papin like protease (PLpro), sprike protein (Spro), human angiotensin converting enzyme-2 (ACE2), and RNA dependent-RNA polymerase (RdRp) yielded binding energies of \u22128.07, \u22128.40, \u22127.55, \u22129.11, and \u22128.69 kcal\/mol, respectively. The electrostatic interaction is the key force in stabilizing the RdRp-rilpivirine complex, while van der Waals interaction dominates in the ACE2 rilpivirine case. Our findings suggest that rilpivirine can inhibit SARS-CoV-2 replication by targeting not only ACE2, but also RdRp and other targets, and therefore, it can be used to invoke altered mechanisms at the pre-entry and post-entry phases.\r\n\r\nConclusion\r\nAs a result of our in silico molecular docking study, we suggest that rilpivirine is a compound that could act as a powerful inhibitor against SARS-CoV-2 targets. Although in vitro and in vivo experiments are needed to verify this prediction we believe that this antiviral drug may be used in preclinical trials to fight against SARS coronavirus.\r\n\r\n","type":"Research","database":"PubMed","created":"2021-07-20"},{"id":2352,"name":"Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs.","author":"Nabeela Farhat, Asad U Khan, ","doi":"10.1007\/s00894-021-04923-w","abstract":"A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.","type":"Research","database":"PubMed","created":"2021-10-01"},{"id":2340,"name":"An updated review on potential therapeutic drug candidates, vaccines and an insight on patents filed for COVID-19.","author":"Rao, G.S.N. KoteswaraGowthami, BuduruNaveen, N. RaghavendraSamudrala, Pavan Kumar","doi":"10.1016\/j.crphar.2021.100063","abstract":"The outbreak of COVID-19 was recognized in December 2019 in China and as of October5th, the pandemic was swept through 216 countries and infected around 34,824,108 individuals, thus posing an unprecedented threat to world's health and economy. Several researchers reported that, a significant mutation in membrane proteins and receptor binding sites of preceding severe acute respiratory syndrome coronavirus (SARS-CoV) to turned as novel SARS-CoV-2 virus and disease was named as COVID-19 (Coronavirus disease 2019). Unfortunately, there is no specific treatment available for COVID-19 patients. The lessons learned from the past management of SARS-CoV and other pandemics, have provided some insights to treat COVID-19. Currently, therapies like anti-viral treatment, immunomodulatory agents, plasma transfusion and supportive intervention etc., are using to treat the COVID-19. Few of these were proven to provide significant therapeutic benefits in treating the COVID-19, however no drug is approved by the regulatory agencies. As the fatality rate is high in patients with comorbid conditions, we have also enlightened the current in-line treatment therapies and specific treatment strategies in comorbid conditions to combat the emergence of COVID-19. In addition, pharmaceutical, biological companies and research institutions across the globe have begun to develop thesafe and effective vaccine for COVID-19. Globally around 170 teams of researchers are racing to develop the COVID-19 vaccine and here we have discussed about their current status of development. Furthermore, recent patents filed in association with COVID-19 was elaborated. This can help many individuals, researchers or health workers, in applying these principles for diagnosis\/prevention\/management\/treatment of the current pandemic.","type":"Review","database":"PMC","created":"2021-10-07"},{"id":2319,"name":"Clinical drug therapies and biologicals currently used or in clinical trial to treat COVID-19.","author":"Malek, Rory J.Bill, Colin A.Vines, Charlotte M.","doi":"10.1016\/j.biopha.2021.112276","abstract":"The potential emergence of SARS-CoV-2 variants capable of escaping vaccine-generated immune responses poses a looming threat to vaccination efforts and will likely prolong the duration of the COVID-19 pandemic. Additionally, the prevalence of beta coronaviruses circulating in animals and the precedent they have set in jumping into human populations indicates that they pose a continuous threat for future pandemics. Currently, only one therapeutic is approved by the U.S. Food and Drug Administration (FDA) for use in treating COVID-19, remdesivir, although other therapies are authorized for emergency use due to this pandemic being a public health emergency. In this review, twenty-four different treatments are discussed regarding their use against COVID-19 and any potential future coronavirus-associated illnesses. Their traditional use, mechanism of action against COVID-19, and efficacy in clinical trials are assessed. Six treatments evaluated are shown to significantly decrease mortality in clinical trials, and ten treatments have shown some form of clinical efficacy.","type":"Review","database":"PMC","created":"2021-10-01"},{"id":2293,"name":"Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease.","author":"Yunxia Xu, Ke Chen, Juanli Pan, Yingshou Lei, Danting Zhang, Lipei Fang, Jinle Tang, Xin Chen, Yanhong Ma, Yi Zheng, Bao Zhang, Yaoqi Zhou, Jian Zhan, Wei Xu, ","doi":"10.1016\/j.ijbiomac.2021.07.184","abstract":"COVID-19 is a disease caused by SARS-CoV-2, which has led to more than 4 million deaths worldwide. As a result, there is a worldwide effort to develop specific drugs for targeting COVID-19. Papain-like protease (PLpro) is an attractive drug target because it has multiple essential functions involved in processing viral proteins, including viral genome replication and removal of post-translational ubiquitination modifications. Here, we established two assays for screening PLpro inhibitors according to protease and anti-ISGylation activities, respectively. Application of the two screening techniques to the library of clinically approved drugs led to the discovery of tanshinone IIA sulfonate sodium and chloroxine with their IC50 values of lower than 10\u00a0\u03bcM. These two compounds were found to directly interact with PLpro and their molecular mechanisms of binding were illustrated by docking and molecular dynamics simulations. The results highlight the usefulness of the two developed screening techniques for locating PLpro inhibitors.","type":"Research","database":"PubMed","created":"2021-08-05"},{"id":2265,"name":"Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial","author":"Jienchi Dorward, Ly-Mee Yu, Gail Hayward, Benjamin R Saville, Oghenekome Gbinigie, Oliver Van Hecke, Emma Ogburn, Philip H Evans, Nicholas PB Thomas, Mahendra G Patel, Duncan Richards, Nicholas Berry, Michelle A Detry, Christina Saunders, Mark Fitzgerald, Victoria Harris, Milensu Shanyinde, Simon de Lusignan, Monique I Andersson, Christopher C Butler, Richard Hobbs","doi":"10.1101\/2021.09.20.21263828","abstract":"Objectives: Colchicine has been proposed as a COVID-19 treatment, but its effect on time to recovery is unknown. We aimed to determine whether colchicine is effective at reducing time to recovery and COVID-19 related hospitalisations\/deaths among people in the community. Design: Prospective, multicentre, open-label, multi-arm, adaptive Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE). Setting: National trial run remotely from a central trial site and at multiple primary care centres across the United Kingdom. Participants: Adults aged [&ge;]65, or [&ge;]18 years with comorbidities or shortness of breath, and unwell [&le;]14 days with suspected COVID-19 in the community. Interventions: Participants were randomised to usual care, usual care plus colchicine (500g daily for 14 days), or usual care plus other interventions. Main outcome measures: The co-primary endpoints were time to first self-reported recovery, and hospitalisation\/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation\/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm). Results: The trial opened on April 2, 2020, with randomisation to colchicine starting on March 04, 2021 and stopping on May 26, 2021, because the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.919 [95% credible interval 0.72 to 1.16] and an estimated increase of 1.14 days [-1.86 to 5.21] in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations\/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 [0.28 to 1.89] and an estimated difference of -0.4% [-2.7% to 2.4]. One serious adverse event occurred in the colchicine group and one in usual care.. Conclusions: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community. Trial registration: ISRCTN86534580.","type":"Research","database":"MedRxiv","created":"2021-09-22"},{"id":2253,"name":"Deleterious drugs in COVID-19: a rapid systematic review and meta-analysis","author":"Michael Holder, Catherine Heeney, Stephen Malden, Uditha Perera,  Aziz Sheikh","doi":"10.1101\/2021.09.17.21262724","abstract":"Background: Concerns have been expressed about a number of drugs that potentially worsen outcomes in patients with COVID-19. We sought to identify all potentially deleterious drug groups in COVID-19 and critically assess the underpinning strength of evidence pertaining to the harmful effects of these drugs. Methods and findings: We performed a rapid systematic review, searching Medline, Embase and two COVID-19 portfolios (WHO COVID-19 database and NIH iSearch COVID-19 portfolio) for papers and preprints related to primary studies investigating drugs identified as potentially deleterious. Primary outcomes were direct measures of susceptibility to infection, disease severity and mortality. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tools. Random-effects meta-analyses were used for data synthesis with further subgroup analyses where possible for specific outcome, study design, statistical adjustment and drug groups when two were combined. Sensitivity analyses were performed by removing any studies at high risk of bias and by publication status. 49 observational studies (15 peer-reviewed papers and 34 preprints) reported primary outcomes for eight drug groups hypothesised to be deleterious. Meta-analysis showed that acute inpatient corticosteroid use was associated with increased mortality (OR 2.22, 95% CI 1.26-3.90), however this result appeared to have been biased by confounding via indication. One subgroup analysis indicated an association between immunosuppressant use and susceptibility to COVID-19 among case control and cross-sectional studies (OR 1.29, 95% CI 1.19-1.40) but this was not found with cohort studies (OR 1.11, 95% CI 0.86-1.43). Studies which adjusted for multiple confounders showed that people taking angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) required a lower level of care (OR 0.85, 95% CI 0.74-0.98). Furthermore, studies which combined these two drug groups in their analysis demonstrated an association with a lower mortality (OR 0.68, 95% CI 0.55-0.85). Conclusions: We found minimal high quality or consistent evidence that any drug groups increase susceptibility, severity or mortality in COVID-19. Converse to initial hypotheses, we found some evidence that regular use of ACEIs and ARBs prior to infection may be effective in reducing the level of care required, such as requiring intensive care, in patients with COVID-19.","type":"Review","database":"MedRxiv","created":"2021-09-20"},{"id":2249,"name":"Nsp2 has the potential to be a drug target revealed by global identification of SARS-CoV-2 Nsp2-interacting proteins.","author":"Yun-Xiao Zheng, Lei Wang, Wei-Sha Kong, Hong Chen, Xue-Ning Wang, Qingfeng Meng, Hai-Nan Zhang, Shu-Juan Guo, He-Wei Jiang, Sheng-Ce Tao, ","doi":"10.1093\/abbs\/gmab088","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)\u2009has become a global health threat since December 2019, and there is still no highly effective drug to control the pandemic. To facilitate drug target identification for drug development, studies on molecular mechanisms, such as SARS-CoV-2 protein interactions, are urgently needed. In this study, we focused on Nsp2, a non-structural protein with largely unknown function and mechanism. The interactome of Nsp2 was revealed through the combination of affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), and 84 proteins of high-confidence were identified. Gene ontology analysis demonstrated that Nsp2-interacting proteins are involved in several biological processes such as endosome transport and translation. Network analysis generated two clusters, including ribosome assembly and vesicular transport. Bio-layer interferometry (BLI) assay confirmed the bindings between Nsp2- and 4-interacting proteins, i.e. STAU2 (Staufen2), HNRNPLL, ATP6V1B2, and RAP1GDS1 (SmgGDS), which were randomly selected from the list of 84 proteins. Our findings provide insights into the Nsp2-host interplay and indicate that Nsp2 may play important roles in SARS-CoV-2 infection and serve as a potential drug target for anti-SARS-CoV-2 drug development.","type":"Research","database":"PubMed","created":null},{"id":2242,"name":"Use of the rheumatic drug tocilizumab for treatment of SARS-CoV-2 patients.","author":"Grygiel-G\u00f3rniak, BognaShaikh, OsamaKumar, Nikita NiranjanHsu, Shao HengSamborski, W\u0142odzimierz","doi":"10.5114\/reum.2021.108554","abstract":"Coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease caused by a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has been observed to vary in its degree of symptoms. One of the most important clinical manifestations is pneumonia and the subsequent worsening of the hyperinflammatory state and cytokine storm.Tocilizumab (TCB) is a recombinant humanized, anti-human monoclonal antibody of the immunoglobulin G1k (IgG1k) subclass that acts against soluble and membrane-bound interleukin six receptors (IL-6R). There is wide use of TCB in rheumatic diseases. However, recently this medication has been used in the treatment of SARS-CoV-2 infection. Tocilizumab application in COVID-19 patients with a high risk of a cytokine storm shows a positive response in reducing the mortality rate. Moreover, TCB minimizes the time needed to recover, improves oxygenation, shortens the duration of vasopressor support, and reduces the likelihood of invasive mechanical ventilation.Therefore we provide an overview of recent studies to understand the efficacy of this drug under various circumstances, including COVID-19 and rheumatic pathologies. This article also explores and integrates the different treatment possibilities in prominent anti-inflammatory and immune-modulatory-related symptoms. The preliminary data demonstrate promising results regarding the efficacy of TCB use in severe COVID-19 patients. Nevertheless, randomized controlled trials, with adequate sample sizes and sufficient follow-up periods, are needed to form conclusions and establish treatment recommendations.","type":"Review","database":"PMC","created":"2021-08-19"},{"id":2223,"name":"Recent progress in the development of potential drugs against SARS-CoV-2.","author":"Chen, JianminAli, FayazKhan, ImranZhu, Yi Zhun","doi":"10.1016\/j.crphar.2021.100057","abstract":"SARS-CoV-2, a newly emerged and highly pathogenic coronavirus, is identified as the causal agent of Coronavirus Disease (2019) (COVID-19) in the late December 2019, in China. The virus has rapidly spread nationwide and spilled over to the other countries around the globe, resulting in more than 120 million infections and 2.6 million deaths until the time of this review. Unfortunately, there are still no specific drugs available against this disease, and it is very necessary to call upon more scientists to work together to stop a further spread. Hence, the recent progress in the development of drugs may help scientific community quickly understand current research status and further develop new effective drugs. Herein, we summarize the cellular entry and replication process of this virus and discuss the recent development of potential viral based drugs that target bio-macromolecules in different stages of the viral life cycle, especially S protein, 3CLPro, PLPro, RdRp and helicase.","type":"Review","database":"PMC","created":"2021-09-13"},{"id":2217,"name":"Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal","author":"Prateek Kumar, Taniya Bhardwaj, Rajanish Giri","doi":"10.1101\/2021.09.14.460211","abstract":"One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed the different spectroscopic technique-based binding assays of an anticancer drug Mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular docking followed by computational simulations with two different forcefields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting NSP1 protein of SARS-CoV-2.","type":"Research","database":"BioRxiv","created":"2021-09-13"},{"id":2216,"name":"Teriflunomide: A possible effective drug for the comprehensive treatment of COVID-19.","author":"Rabie, Amgad M.","doi":"10.1016\/j.crphar.2021.100055","abstract":"The coronavirus disease 2019 (COVID-19) pandemic has undoubtedly become a global crisis. Consequently, discovery and identification of new or known potential drug candidates to solve the health problems caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become an urgent necessity. This current research study sheds light on the possible direct repurposing of the antirheumatic drug teriflunomide to act as an effective and potent anti-SARS-CoV-2 agent. Herein, an interesting computational molecular docking study of teriflunomide, to investigate and evaluate its potential inhibitory activities on the novel coronaviral-2 RNA-dependent RNA polymerase (nCoV-RdRp) protein, was reported. The docking procedures were accurately carried out on nCoV-RdRp (with\/without RNA) using the COVID-19 Docking Server, through adjusting it on the small molecule docking mode. Remdesivir and its active metabolite (GS-441524) were used as the active references for the comparison and evaluation purpose. Interestingly, the computational docking analysis of the best inhibitory binding mode of teriflunomide in the binding pocket of the active site of the SARS-CoV-2 RdRp revealed that teriflunomide may exhibit significantly stronger inhibitory binding interactions and better inhibitory binding affinities (teriflunomide has considerably lower binding energies of \u22129.70 and \u22127.80\u00a0kcal\/mol with RdRp-RNA and RdRp alone, respectively) than both references. It was previously reported that teriflunomide strongly inhibits the viral replication and reproduction through two mechanisms of action, thus the results obtained in the present study surprisingly supports the double mode of antiviral action of this antirheumatic ligand. In conclusion, the current research paved the way to practically prove the hypothetical theory of the promising abilities of teriflunomide to successfully attack the SARS-CoV-2 particles and inhibit their replication in a triple mode of action through integrating the newly-discovered nCoV-RdRp-inhibiting properties with the previously-known two anticoronaviral mechanisms of action. Based on the previous interesting facts and results, the triple SARS-CoV-2\/sextet COVID-19 attacker teriflunomide can further undergo in vitro\/in vivo anti-COVID-19 assays together with preclinical\/clinical studies and trials in an attempt to evaluate and prove its comprehensive pharmacological activities against the different SARS-CoV-2 strains to be effectively used in COVID-19 therapy in the very near future.","type":"Research","database":"PMC","created":"2021-09-10"},{"id":2215,"name":"Candidate antiviral drugs for COVID-19 and their environmental implications: a comprehensive analysis.","author":"Biswas, ParthaHasan, Mohammad MehediDey, Diptados Santos Costa, Ana CarlaPolash, Shakil AhmedBibi, ShabanaFerdous, NadimKaium, Md. AbuRahman, MD. HasanurJeet, Fardin KamalPapadakos, StavrosIslam, KhairulUddin, Md. Sahab","doi":"10.1007\/s11356-021-16096-3","abstract":"Emerging from Wuhan, China, SARS-CoV-2 is the new global threat that killed millions of people, and many are still suffering. This pandemic has not only affected people but also caused economic crisis throughout the world. Researchers have shown good progress in revealing the molecular insights of SARS-CoV-2 pathogenesis and developing vaccines, but effective treatment against SARS-CoV-2-infected patients are yet to be found. Several vaccines are available and used in many countries, while many others are still in clinical or preclinical studies. However, this involves a long-term process, considering the safety procedures and requirements and their long-term protection capacity and in different age groups are still questionable. Therefore, at present, the drug repurposing of the existing therapeutics previously designed against other viral diseases seems to be the only practical approach to mitigate the current situation. The safety of most of these therapeutic agents has already been tested. Recent clinical reports revealed promising therapeutic efficiency of several drugs such as remdesivir, tenofovir disoproxil fumarate, azithromycin, lopinavir\/ritonavir, chloroquine, baricitinib, and cepharanthine. Besides, plasma therapies were used to treat patients and prevent fatal outcomes. Thus, in this article, we have summarized the epidemiological and clinical data from several clinical trials conducted since the beginning of the pandemic, emphasizing the efficiency of the known agents against SARS-CoV-2 and their harmful side effects on the human body as well as their environmental implications. This review shows a clear overview of the current pharmaceutical perspective on COVID-19 treatment.","type":"Research","database":"PMC","created":"2021-09-11"},{"id":2195,"name":"Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry.","author":"Duarte, Rodrigo R. R.Copertino, Dennis C.I\u00f1iguez, Luis P.Marston, Jez L.Bram, YaronHan, YulingSchwartz, Robert E.Chen, ShuibingNixon, Douglas F.Powell, Timothy R.","doi":"10.1186\/s10020-021-00356-6","abstract":"Background: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. Methods: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and\u00a0molecular docking analyses, with\u00a0in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. Results: Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2\u2019s main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. Conclusions: Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and\u00a0supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics. Supplementary Information: The online version contains supplementary material available at 10.1186\/s10020-021-00356-6.","type":"Research","database":"PMC","created":"2021-09-08"},{"id":2174,"name":"Drug repurposing against coronavirus disease 2019 (COVID-19): A review.","author":"Luo, LianxiangQiu, QinHuang, FangfangLiu, KaifengLan, YongqiLi, XiaolingHuang, YugeCui, LiaoLuo, Hui","doi":"10.1016\/j.jpha.2021.09.001","abstract":"Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been found to be the culprit in the coronavirus disease (COVID-19), causing a global pandemic. Despite the existence of many vaccine programs, the number of confirmed cases and fatalities due to COVID-19 is still increasing. Furthermore, a number of variants have been reported. Because of the absence of approved anti-coronavirus drugs, the treatment and management of COVID-19 has become a global challenge. Under these circumstances, drug repurposing is an effective method to identify candidate drugs with a shorter cycle of clinical trials. Here, we summarize the current status of the application of drug repurposing in COVID-19, including drug repurposing based on virtual computer screening, network pharmacology, and bioactivity, which may be beneficial COVID-19 treatment.","type":"Review","database":"PMC","created":"2021-09-03"},{"id":2101,"name":"Bias as a source of inconsistency in ivermectin trials for COVID-19: A systematic review","author":"Ariel Izcovich, Sasha Peiris, Mart\u00edn Ragusa, Fernando Tortosa, Gabriel Rada, Sylvain Aldighieri, Ludovic Reveiz","doi":"10.1101\/2021.08.19.21262304","abstract":"Background and purpose The objective of this systematic review is to summarize the effects of ivermectin for the prevention and treatment of patients with COVID-19 and to assess inconsistencies in results from individual studies with focus on risk of bias due to methodological limitations. Evidence review We searched the L.OVE platform through July 6, 2021 and included randomized trials (RCTs) comparing ivermectin to standard or other active treatments. We conducted random-effects pairwise meta-analysis, assessed the certainty of evidence using the GRADE approach and performed sensitivity analysis excluding trials with risk of bias. Results We included 29 RCTs which enrolled 5592 cases. Overall, the certainty of the evidence was very low to low. Compared to standard of care, ivermectin may reduce mortality, may increase symptom resolution or improvement, may increase viral clearance, may reduce infections in exposed individuals and may decrease hospitalizations (Risk difference (RD) 21 fewer per 1000, 95%CI: 35 fewer to 4 more). However, after excluding trials classified as ''high risk'' or ''some concerns'' in the risk of bias assessment, most estimates of effect changed substantially: Compared to standard of care, low certainty evidence suggests that ivermectin may not significantly reduce mortality (RD 7 fewer per 1000, 95%CI: 77 fewer to 108 more) nor mechanical ventilation (RD 6 more per 1000, 95%CI: 43 fewer to 86 more), and moderate certainty evidence shows that it probably does not significantly increase symptom resolution or improvement (RD 14 more per 1000, 95%CI: 29 fewer to 71 more) nor viral clearance (RD 12 fewer per 1000, 95%CI: 84 fewer to 76 more). It is uncertain if ivermectin increases or decreases severe adverse events and symptomatic infections in exposed individuals. Conclusions and Relevance Ivermectin may not improve clinically important outcomes in patients with COVID-19 and its effects as a prophylactic intervention in exposed individuals are uncertain. Previous reports concluding significant benefits associated with ivermectin are based on potentially biased results reported by studies with substantial methodological limitations. Further research is needed.","type":"Review","database":"MedRxiv","created":"2021-08-20"},{"id":2074,"name":"Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2.","author":"Franck Touret, Jean-S\u00e9lim Driouich, Maxime Cochin, Paul R\u00e9mi Petit, Magali Gilles, Karine Barth\u00e9l\u00e9my, Gr\u00e9gory Moureau, Francois-Xavier Mahon, Denis Malvy, Caroline Solas, Xavier de Lamballerie, Antoine Nougair\u00e8de, ","doi":"10.1016\/j.antiviral.2021.105137","abstract":"Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of imatinib in multiple models. Our results indicated that imatinib and another TKI, the masitinib, exhibit an antiviral activity in VeroE6 cells. However, imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of imatinib and similar TKIs as antivirals in the treatment of Covid-19.","type":"Research","database":"PubMed","created":"2021-07-11"},{"id":2058,"name":"Oral disease-modifying antirheumatic drugs and immunosuppressants with antiviral potential, including SARS-CoV-2 infection: a review.","author":"Tsai, Y. C.Tsai, T. F.","doi":"10.1177\/1759720X20947296","abstract":"There have been several episodes of viral infection evolving into epidemics in recent decades, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the latest example. Its high infectivity and moderate mortality have resulted in an urgent need to find an effective treatment modality. Although the category of immunosuppressive drugs usually poses a risk of infection due to interference of the immune system, some of them have been found to exert antiviral properties and are already used in daily practice. Recently, hydroxychloroquine and baricitinib have been proposed as potential drugs for SARS-CoV-2. In fact, there are other immunosuppressants known with antiviral activities, including cyclosporine A, hydroxyurea, minocycline, mycophenolic acid, mycophenolate mofetil, leflunomide, tofacitinib, and thalidomide. The inherent antiviral activity could be a treatment choice for patients with coexisting rheumatological disorders and infections. Clinical evidence, their possible mode of actions and spectrum of antiviral activities are included in this review article.Lay summary: Immunosuppressants often raise the concern of infection risks, especially for patients with underlying immune disorders. However, some disease-modifying antirheumatic drugs (DMARDs) with inherent antiviral activity would be a reasonable choice in the situation of concomitant viral infections and flare up of autoimmune diseases. This review covers DMARDs of treatment potential for SARS-CoV-2 in part I, and antiviral mechanisms plus trial evidence for viruses other than SARS-CoV-2 in part II.","type":"Review","database":"PMC","created":"2020-09-02"},{"id":2041,"name":"Potential Drugs and Remedies for the Treatment of COVID-19: a Critical Review.","author":"Barati, FatemehPouresmaieli, MahdiEkrami, ElenaAsghari, SaharZiarani, Farzad RamezaniMamoudifard, Matin","doi":"10.1186\/s12575-020-00129-1","abstract":"Abstract: COVID-19 disease with a high rate of contagious and highly nonspecific symptoms, is an infectious disease caused by a newly discovered coronavirus. Most people who fall sick with COVID-19 will experience mild to moderate symptoms such as respiratory symptoms, cough, dyspnea, fever, and viral pneumonia and recover without any special cure. However, some others need special and emergency treatment to get rid of this widespread disease. Till now, there are numbers of proposed novel compounds as well as standards therapeutics agent existed for other conditions seems to have efficacy against the 2019-nCoV. Some which are being tested for MERS-CoV and SARS-CoV are validated that could be also efficient against this new coronavirus. However, there are currently no effective specific antivirals or drug combinations introduced for 2019-nCoV specifically that be supported by high-level evidence. The main purpose of this paper is to review typical and ongoing treatments for coronavirus disease including home remedies, herbal medicine, chemical drugs, plasma therapy, and also vaccinies. In this regards, famous herbal medicines and common chemical drugs which are routinely to be prescribed for patients are introduced. Moreover, a section is assigned to the drug interactions and some outdated drugs which have been proved to be inefficient. We hope that this work could pave the way for researchers to develop faster and more reliable methods for earlier treatment of patients and rescue more people. Graphical abstract:","type":"Review","database":"PMC","created":"2020-07-22"},{"id":2028,"name":"An Updated Review of Computer-Aided Drug Design and Its Application to COVID-19.","author":"Gurung, Arun BahadurAli, Mohammad AjmalLee, JoongkuFarah, Mohammad AbulAl-Anazi, Khalid Mashay","doi":"10.1155\/2021\/8853056","abstract":"The recent outbreak of the deadly coronavirus disease 19 (COVID-19) pandemic poses serious health concerns around the world. The lack of approved drugs or vaccines continues to be a challenge and further necessitates the discovery of new therapeutic molecules. Computer-aided drug design has helped to expedite the drug discovery and development process by minimizing the cost and time. In this review article, we highlight two important categories of computer-aided drug design (CADD), viz., the ligand-based as well as structured-based drug discovery. Various molecular modeling techniques involved in structure-based drug design are molecular docking and molecular dynamic simulation, whereas ligand-based drug design includes pharmacophore modeling, quantitative structure-activity relationship (QSARs), and artificial intelligence (AI). We have briefly discussed the significance of computer-aided drug design in the context of COVID-19 and how the researchers continue to rely on these computational techniques in the rapid identification of promising drug candidate molecules against various drug targets implicated in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The structural elucidation of pharmacological drug targets and the discovery of preclinical drug candidate molecules have accelerated both structure-based as well as ligand-based drug design. This review article will help the clinicians and researchers to exploit the immense potential of computer-aided drug design in designing and identification of drug molecules and thereby helping in the management of fatal disease.","type":"Review","database":"PMC","created":"2021-06-23"},{"id":2025,"name":"Roles of existing drug and drug targets for COVID-19 management.","author":"Ayele, Akeberegn GoremsEnyew, Engidaw FentahunKifle, Zemene Demelash","doi":"10.1016\/j.metop.2021.100103","abstract":"In December 2019, a highly transmissible, pneumonia epidemic caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), erupted in China and other countries, resulting in devastation and health crisis worldwide currently. The search and using existing drugs support to curb the current highly contagious viral infection is spirally increasing since the pandemic began. This is based on these drugs had against other related RNA-viruses such as MERS\u2013Cov, and SARS-Cov. Moreover, researchers are scrambling to identify novel drug targets and discover novel therapeutic options to vanquish the current pandemic. Since there is no definitive treatment to control Covid-19 vaccines are remain to be a lifeline. Currently, many vaccine candidates are being developed with most of them are reported to have positive results. Therapeutic targets such as helicases, transmembrane serine protease 2, cathepsin L, cyclin G-associated kinase, adaptor-associated kinase 1, two-pore channel, viral virulence factors, 3-chymotrypsin-like protease, suppression of excessive inflammatory response, inhibition of viral membrane, nucleocapsid, envelope, and accessory proteins, and inhibition of endocytosis were identified as a potential target against COVID-19 infection. This review also summarizes plant-based medicines for the treatment of COVID-19 such as saposhnikoviae divaricata, lonicerae japonicae flos, scutellaria baicalensis, lonicera japonicae, and some others. Thus, this review aimed to focus on the most promising therapeutic targets being repurposed against COVID-19 and viral elements that are used in COVID-19 vaccine candidates.","type":"Review","database":"PMC","created":"2021-06-28"},{"id":2015,"name":"Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021.","author":"Alam, SafaetKamal, Taslima BinteSarker, Md. Moklesur RahmanZhou, Jin-RongRahman, S. M. AbdurMohamed, Isa Naina","doi":"10.3389\/fphar.2021.659577","abstract":"COVID-19, transmitted by SARS-CoV-2, is one of the most serious pandemic situations in the history of mankind, and has already infected a huge population across the globe. This horrendously contagious viral outbreak was first identified in China and within a very short time it affected the world's health, transport, economic, and academic sectors. Despite the recent approval of a few anti-COVID-19 vaccines, their unavailability and insufficiency along with the lack of other potential therapeutic options are continuing to worsen the situation, with valuable lives continuing to be lost. In this situation, researchers across the globe are focusing on repurposing prospective drugs and prophylaxis such as favipiravir, remdesivir, chloroquine, hydroxychloroquine, ivermectin, lopinavir-ritonavir, azithromycin, doxycycline, ACEIs\/ARBs, rivaroxaban, and protease inhibitors, which were preliminarily based on in vitro and in vivo pharmacological and toxicological study reports followed by clinical applications. Based on available preliminary data derived from limited clinical trials, the US National Institute of Health (NIH) and USFDA also recommended a few drugs to be repurposed i.e., hydroxychloroquine, remdesivir, and favipiravir. However, World Health Organization later recommended against the use of chloroquine, hydroxychloroquine, remdesivir, and lopinavir\/ritonavir in the treatment of COVID-19 infections. Combining basic knowledge of viral pathogenesis and pharmacodynamics of drug molecules as well as in silico approaches, many drug candidates have been investigated in clinical trials, some of which have been proven to be partially effective against COVID-19, and many of the other drugs are currently under extensive screening. The repurposing of prospective drug candidates from different stages of evaluation can be a handy wellspring in COVID-19 management and treatment along with approved anti-COVID-19 vaccines. This review article combined the information from completed clinical trials, case series, cohort studies, meta-analyses, and retrospective studies to focus on the current status of repurposing drugs in 2021.","type":"Review","database":"PMC","created":"2021-06-13"},{"id":2009,"name":"Mefloquine, a Potent Anti-severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Drug as an Entry Inhibitor in vitro.","author":"Shionoya, KahoYamasaki, MasakoIwanami, ShoyaIto, YusukeFukushi, ShuetsuOhashi, HirofumiSaso, WakanaTanaka, TomohiroAoki, ShinKuramochi, KoujiIwami, ShingoTakahashi, YoshimasaSuzuki, TadakiMuramatsu, MasamichiTakeda, MakotoWakita, TakajiWatashi, Koichi","doi":"10.3389\/fmicb.2021.651403","abstract":"Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic\/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6\/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 \u03bcM, IC90 = 2.31 \u03bcM, and IC99 = 4.39 \u03bcM in VeroE6\/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.","type":"Research","database":"PMC","created":"2021-04-29"},{"id":2001,"name":"Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system.","author":"Yuan, ShuofengChan, Jasper F.W.Chik, Kenn K.H.Chan, Chris C.Y.Tsang, Jessica O.L.Liang, RonghuiCao, JianliTang, KaimingChen, Lin-LeiWen, KunCai, Jian-PiaoYe, Zi-WeiLu, GangChu, HinJin, Dong-YanYuen, Kwok-Yung","doi":"10.1016\/j.phrs.2020.104960","abstract":"Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5\u201310 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and\/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50 % maximal effective concentrations (EC50) that exceeded their achievable peak serum concentrations (Cmax), side effects, and\/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC50 1.13\u20132.01 \u03bcM). Bexarotene demonstrated the highest Cmax:EC50 ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.","type":"Research","database":"PMC","created":"2020-05-27"},{"id":1993,"name":"COVID-19: Vaccine Delivery System, Drug Repurposing and Application of Molecular Modeling Approach.","author":"Abd El Hadi, Soha RZien El-Deen, Esmat EBahaa, Mostafa MSadakah, Abdelfattah AYassin, Heba A","doi":"10.2147\/DDDT.S320320","abstract":"The acute respiratory syndrome coronavirus (SARS-CoV-2) has spread across the world, resulting in a pandemic COVID-19 which is a human zoonotic disease that is caused by a novel coronavirus (CoV) strain thought to have originated in wild or captive bats in the initial COVID outbreak region. The global COVID-19 outbreak started in Guangdong Province, China\u2019s southernmost province. The global response to the COVID-19 pandemic has been hampered by the sheer number of infected people, many of whom need intensive care before succumbing to the disease. The epidemic is being handled by a combination of disease control by public health interventions and compassionate treatment for those who have been impacted. There is no clear anti-COVID-19 medication available at this time. However, the need to find medications that can turn the tide has led to the development of a number of investigational drugs as potential candidates for improving outcomes, especially in the severely and critically ill. Although many of these adjunctive medications are still being studied in clinical trials, professional organizations have attempted to define the circumstances in which their use is deemed off-label or compassionate. It is important to remind readers that new information about COVID-19\u2019s clinical features, treatment options, and outcomes is released on a regular basis. The mainstay of treatment remains optimized supportive care, and the therapeutic effectiveness of the subsequent agents is still being studied.","type":"Review","database":"PMC","created":"2021-07-29"},{"id":1990,"name":"Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor.","author":"Maurya, Vimal K.Kumar, SwatantraPrasad, Anil K.Bhatt, Madan L. B.Saxena, Shailendra K.","doi":"10.1007\/s13337-020-00598-8","abstract":"The recent outbreak of COVID-19 caused by SARS-CoV-2 brought a great global public health and economic concern. SARS-CoV-2 is an enveloped RNA virus, from the genus Betacoronavirus. Although few molecules have been tested and shown some efficacy against SARS-CoV-2 in humans but a safe and cost-effective attachment inhibitors are still required for the treatment of COVID-19. Natural products are gaining attention because of the large therapeutic window and potent antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties. Therefore, this study was planned to screen natural products from Ayurveda\u00a0that have the potential to modulate host immune system as well as block the virus entry in host cells by interfering its interaction with cellular receptor and may be used to develop an effective and broad-spectrum strategy for the management of COVID-19 as well as other coronavirus infections in coming future. To decipher the antiviral activity of the selected natural products, molecular docking was performed. Further, the drug-likeness, pharmacokinetics and toxicity parameters of the selected natural products were determined. Docking results suggest that curcumin and nimbin exhibits highest interaction with spike glycoprotein (MolDock score \u2212\u2009141.36 and \u2212\u2009148.621\u00a0kcal\/mole) and ACE2 receptor (MolDock score \u2212\u2009142.647 and \u2212\u2009140.108\u00a0kcal\/mole) as compared with other selected natural products\/drugs and controls. Also, the pharmacokinetics data illustrated that all selected natural products have better pharmacological properties (low molecular weight; no violation of Lipinski rule of five, good absorption profiles, oral bioavailability, good blood\u2013brain barrier penetration, and low toxicity risk). Our study exhibited that curcumin, nimbin, withaferin A, piperine, mangiferin, thebaine, berberine, and andrographolide have significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and\/or prophylactic agent for restricting viral attachment to the host cells. However, few other natural products like resveratrol, quercetin, luteolin, naringenin, zingiberene, and gallic acid has the significant binding affinity towards ACE2 receptor only and therefore may be used for ACE2-mediated attachment inhibition of SARS-CoV-2.","type":"Research","database":"PMC","created":"2020-05-23"},{"id":1985,"name":"Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm.","author":"Rabaan, Ali A.Al-Ahmed, Shamsah H.Muhammad, JavedKhan, AmjadSule, Anupam ATirupathi, RaghavendraMutair, Abbas AlAlhumaid, SaadAl-Omari, AwadDhawan, ManishTiwari, RuchiSharun, KhanMohapatra, Ranjan K.Mitra, SaikatBilal, MuhammadAlyami, Salem A.Emran, Talha BinMoni, Mohammad AliDhama, Kuldeep","doi":"10.3390\/vaccines9050436","abstract":"Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-\u03b1, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK\/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines\u2019 molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.","type":"Review","database":"PMC","created":"2021-04-28"},{"id":1982,"name":"Drug repurposing for COVID-19: Approaches, challenges and promising candidates.","author":"Ng, Yan LingSalim, Cyrill KafiChu, Justin Jang Hann","doi":"10.1016\/j.pharmthera.2021.107930","abstract":"Traditional drug development and discovery has not kept pace with threats from emerging and re-emerging diseases such as Ebola virus, MERS-CoV and more recently, SARS-CoV-2. Among other reasons, the exorbitant costs, high attrition rate and extensive periods of time from research to market approval are the primary contributing factors to the lag in recent traditional drug developmental activities. Due to these reasons, drug developers are starting to consider drug repurposing (or repositioning) as a viable alternative to the more traditional drug development process. Drug repurposing aims to find alternative uses of an approved or investigational drug outside of its original indication. The key advantages of this approach are that there is less developmental risk, and it is less time-consuming since the safety and pharmacological profile of the repurposed drug is already established. To that end, various approaches to drug repurposing are employed. Computational approaches make use of machine learning and algorithms to model disease and drug interaction, while experimental approaches involve a more traditional wet-lab experiments. This review would discuss in detail various ongoing drug repurposing strategies and approaches to combat the current COVID-19 pandemic, along with the advantages and the potential challenges.","type":"Review","database":"PMC","created":"2021-06-22"},{"id":1975,"name":"Repurposing Drugs, Ongoing Vaccine, and New Therapeutic Development Initiatives Against COVID-19.","author":"Saha, Rudra P.Sharma, Ashish RanjanSingh, Manoj K.Samanta, SaikatBhakta, SwarnavMandal, SnehasishBhattacharya, ManojitLee, Sang-SooChakraborty, Chiranjib","doi":"10.3389\/fphar.2020.01258","abstract":"As the COVID-19 is still growing throughout the globe, a thorough investigation into the specific immunopathology of SARS-CoV-2, its interaction with the host immune system and pathogen evasion mechanism may provide a clear picture of how the pathogen can breach the host immune defenses in elderly patients and patients with comorbid conditions. Such studies will also reveal the underlying mechanism of how children and young patients can withstand the disease better. The study of the immune defense mechanisms and the prolonged immune memory from patients population with convalescent plasma may help in designing a suitable vaccine candidate not only for the current outbreak but also for similar outbreaks in the future. The vital drug candidates, which are being tested as potential vaccines or therapeutics against COVID-19, include live attenuated vaccine, inactivated or killed vaccine, subunit vaccine, antibodies, interferon treatment, repurposing existing drugs, and nucleic acid-based vaccines. Several organizations around the world have fast-tracked the development of a COVID-19 vaccine, and some drugs already went to phase III of clinical trials. Hence, here, we have tried to take a quick glimpse of the development stages of vaccines or therapeutic approaches to treat this deadly disease.","type":"Review","database":"PMC","created":"2020-08-18"},{"id":1970,"name":"Systematic review on role of structure based drug design (SBDD) in the identification of anti-viral leads against SARS-Cov-2.","author":"Bajad, Nilesh GajananRayala, SwethaGutti, GopichandSharma, AnjaliSingh, MeenakshiKumar, AshokSingh, Sushil Kumar","doi":"10.1016\/j.crphar.2021.100026","abstract":"The outbreak of existing public health distress is threatening the entire world with emergence and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel coronavirus disease 2019 (COVID-19) is mild in most people. However, in some elderly people with co-morbid conditions, it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction leading to death. COVID-19 has caused global panic in the healthcare sector and has become one of the biggest threats to the global economy. Drug discovery researchers are expected to contribute rapidly than ever before. The complete genome sequence of coronavirus had been reported barely a month after the identification of first patient. Potential drug targets to combat and treat the coronavirus infection have also been explored. The iterative structure-based drug design (SBDD) approach could significantly contribute towards the discovery of new drug like molecules for the treatment of COVID-19. The existing antivirals and experiences gained from SARS and MERS outbreaks may pave way for identification of potential drug molecules using the approach. SBDD has gained momentum as the essential tool for faster and costeffective lead discovery of antivirals in the past. The discovery of FDA approved human immunodeficiency virus type 1 (HIV-1) inhibitors represent the foremost success of SBDD. This systematic review provides an overview of the novel coronavirus, its pathology of replication, role of structure based drug design, available drug targets and recent advances in in-silico drug discovery for the prevention of COVID-19. SARSCoV- 2 main protease, RNA dependent RNA polymerase (RdRp) and spike (S) protein are the potential targets, which are currently explored for the drug development.","type":"Review","database":"PMC","created":"2021-05-13"},{"id":1962,"name":"Antivirals Against Coronaviruses: Candidate Drugs for SARS-CoV-2 Treatment?","author":"Santos, Igor de AndradeGrosche, Vict\u00f3ria RiquenaBergamini, Fernando Rodrigues GoulartSabino-Silva, RobinsonJardim, Ana Carolina Gomes","doi":"10.3389\/fmicb.2020.01818","abstract":"Coronaviruses (CoVs) are a group of viruses from the family Coronaviridae that can infect humans and animals, causing mild to severe diseases. The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a global threat, urging the development of new therapeutic strategies. Here we present a selection of relevant compounds that have been described from 2005 until now as having in vitro and\/or in vivo antiviral activities against human and\/or animal CoVs. We also present compounds that have reached clinical trials as well as further discussing the potentiality of other molecules for application in (re)emergent CoVs outbreaks. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential SARS-CoV-2 drug candidates.","type":"Review","database":"PMC","created":"2020-08-12"},{"id":1961,"name":"SARS-CoV-2 spike protein and RNA dependent RNA polymerase as targets for drug and vaccine development: A review.","author":"Muhammed, YusufYusuf Nadabo, AbduljalalPius, MkpoutoSani, BashiruUsman, JafarAnka Garba, NasirMohammed Sani, JaafaruOpeyemi Olayanju, BasitZeal Bala, SundayGarba Abdullahi, MusaSambo, Misbahu","doi":"10.1016\/j.bsheal.2021.07.003","abstract":"The present pandemic has posed a crisis to the economy of the world and the health sector. Therefore, the race to expand research to understand some good molecular targets for vaccine and therapeutic development for SARS-CoV-2 is inevitable. The newly discovered coronavirus 2019 (COVID-19) is a positive sense, single-stranded RNA, and enveloped virus, assigned to the beta CoV genus. The virus (SARS-CoV-2) is more infectious than the previously detected coronaviruses (MERS and SARS). Findings from many studies have revealed that S protein and RdRp are good targets for drug repositioning, novel therapeutic development (antibodies and small molecule drugs), and vaccine discovery. Therapeutics such as chloroquine, convalescent plasma, monoclonal antibodies, spike binding peptides, and small molecules could alter the ability of S protein to bind to the ACE-2 receptor, and drugs such as remdesivir (targeting SARS-CoV-2 RdRp), favipir, and Emetine could prevent SASR-CoV-2 RNA synthesis. The novel vaccines such as mRNA1273 (Moderna), 3LNP-mRNAs (Pfizer\/BioNTech), and ChAdOx1-S (University of Oxford\/Astra Zeneca) targeting S protein have proven to be effective in combating the present pandemic. Further exploration of the potential of S protein and RdRp is crucial in fighting the present pandemic.","type":"Review","database":"PMC","created":"2021-07-20"},{"id":1949,"name":"An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease.","author":"Nemanja Djokovic, Dusan Ruzic, Teodora Djikic, Sandra Cvijic, Jelisaveta Ignjatovic, Svetlana Ibric, Katarina Baralic, Aleksandra Buha Djordjevic, Marijana Curcic, Danijela Djukic-Cosic, Katarina Nikolic, ","doi":"10.1002\/minf.202000187","abstract":"Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (M<sup>pro<\/sup> ). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association. Through presented approach, we selected the most promising FDA approved drugs for further COVID-19 drug development campaigns and analysed them in context of available experimental data. To the best of our knowledge, this is unique in silico study which integrates structure-based molecular modeling of M<sup>pro<\/sup> inhibitors with predictions of their tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.","type":"Research","database":"PubMed","created":"2021-03-29"},{"id":1945,"name":"Ceftazidime is a potential drug to inhibit SARS-CoV-2 infection in vitro by blocking spike protein-ACE2 interaction.","author":"ChangDong Lin, Yue Li, YueBin Zhang, ZhaoYuan Liu, Xia Mu, Chenjian Gu, Jing Liu, Yutang Li, GuoHui Li, JianFeng Chen, ","doi":"10.1038\/s41392-021-00619-y","abstract":null,"type":"Other","database":"PubMed","created":"2021-05-17"},{"id":1915,"name":"Identification of known drugs as potential SARS-CoV-2 Mpro inhibitors using ligand- and structure-based virtual screening.","author":"Leonardo Bruno Federico, Guilherme Martins Silva, Lorane Izabel da Silva Hage-Melim, Suzane Quintana Gomes, Mariana Pegrucci Barcelos, Isaque Ant\u00f4nio Galindo Francischini, Carlos Henrique Tomich de Paula da Silva, ","doi":"10.4155\/fmc-2021-0025","abstract":"Background:\r\nThe new coronavirus pandemic has had a significant\u00a0impact worldwide, and therapeutic treatment for this viral infection is being strongly pursued. Efforts have been undertaken by medicinal chemists to discover molecules or known drugs that may be\u00a0effective in COVID-19 treatment - in particular, targeting the main protease (Mpro) of the virus.\r\nMaterials & methods: We have employed an innovative strategy - application of ligand- and structure-based virtual screening - using a special compilation of an approved and diverse set of SARS-CoV-2 crystallographic complexes that was\u00a0recently published. \r\nResults and conclusion: We identified seven drugs with different original indications\u00a0that might act as potential Mpro inhibitors and may be preferable to other drugs that have been repurposed. These drugs will be experimentally tested to confirm their potential Mpro inhibition and thus their effectiveness against COVID-19.","type":"Research","database":"PubMed","created":"2021-06-24"},{"id":1894,"name":"Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study.","author":"Mahmoud A A Ibrahim, Eslam A R Mohamed, Alaa H M Abdelrahman, Khaled S Allemailem, Mahmoud F Moustafa, Ahmed M Shawky, Ali Mahzari, Abdulrahim Refdan Hakami, Khlood A A Abdeljawaad, Mohamed A M Atia, ","doi":"10.1016\/j.jmgm.2021.107904","abstract":"Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (M<sup>pro<\/sup>) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 M<sup>pro<\/sup> using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards M<sup>pro<\/sup> with docking scores less than\u00a0-9.0\u00a0kcal\/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM\/GBSA) binding energy calculations, were performed for the top potent analogs in complex with M<sup>pro<\/sup>. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 M<sup>pro<\/sup> over 150 ns MD course with \u0394G<sub>binding<\/sub> values of\u00a0-69.0 and\u00a0-68.1\u00a0kcal\/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 M<sup>pro<\/sup> active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 M<sup>pro<\/sup> inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM\/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.","type":"Research","database":"PubMed","created":"2021-03-19"},{"id":1888,"name":"Candidate drugs against SARS-CoV-2 and COVID-19.","author":"Dwight L McKee, Ariane Sternberg, Ulrike Stange, Stefan Laufer, Cord Naujokat, ","doi":"10.1016\/j.phrs.2020.104859","abstract":"Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019\/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.","type":"Review","database":"PubMed","created":"2020-04-28"},{"id":1880,"name":"Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19.","author":"Xiuhong Zhang, Yan Zhang, Weizhen Qiao, Ji Zhang, Zhigang Qi, ","doi":"10.1016\/j.intimp.2020.106749","abstract":"In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2\u00a0weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1\/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.","type":"Research","database":"PubMed","created":"2020-06-30"},{"id":1878,"name":"Current approaches for target-specific drug discovery using natural compounds against SARS-CoV-2 infection.","author":"Prashant Khare, Utkarsha Sahu, Satish Chandra Pandey, Mukesh Samant, ","doi":"10.1016\/j.virusres.2020.198169","abstract":"The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) recently caused a pandemic outbreak called coronavirus disease 2019 (COVID-19). This disease has initially been reported in China and also now it is expeditiously spreading around the globe directly among individuals through coughing and sneezing. Since it is a newly emerging viral disease and obviously there is a lack of anti-SARS-CoV-2 therapeutic agents, it is urgently required to develop an effective anti-SARS-CoV-2-agent.Through recent advancements in computational biology and biological assays, several natural compounds and their derivatives have been reported to confirm their target specific antiviral potential against Middle East respiratory syndrome coronavirus (MERS-CoV) or Severe Acute Respiratory Syndrome(SARS-CoV).These targets including an important host cell receptor, i.e., angiotensin-converting enzyme ACE2 and several viral proteins e.g. spike glycoprotein (S) containing S1 and S2 domains, SARS CoV Chymotrypsin-like cysteine protease (3CL<sup>pro<\/sup>), papain-like cysteine protease (PL<sup>pro<\/sup>), helicases and RNA-dependent RNA polymerase (RdRp). Due to physical, chemical, and some genetic similarities of SARS CoV-2 with SARS-COV and MERS-COV, repurposing various anti-SARS-COV or anti-MERS-COV natural therapeutic agents could be helpful for the development of anti-COVID-19 herbal medicine. Here we have summarized various drug targets in SARS-COV and MERS-COV using several natural products and their derivatives, which could guide researchers to design and develop a safe and cost-effective anti-SARS-COV-2 drugs.","type":"Review","database":"PubMed","created":"2020-09-23"},{"id":1877,"name":"A Review on the Effectivity of the Current COVID-19 Drugs and Vaccines: Are They Really Working Against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants?","author":"Rashed Noor, ","doi":"10.1007\/s40588-021-00172-w","abstract":"In order to eradicate the COVID-19 pandemic, scientists around the world have been working very hard for a year or more with the motto of designing effective drugs and vaccines against the severe acute respiratory coronavirus 2 (SARS-CoV-2). Along with the positive results with the antiviral drugs and a few commercialized vaccines, the unresponsiveness as well as some side effects of such therapies have also been noticed, possibly due to the emergence of the SARS-CoV-2 variants. Therefore, current review summarized the actual effectiveness of the antivirals and vaccines which are in current use for the treatment of the COVID-19 patients.","type":"Review","database":"PubMed","created":"2021-07-02"},{"id":1870,"name":"Targeting SARS-CoV-2 Main Protease: A Computational Drug Repurposing Study.","author":"Krishnaprasad Baby, Swastika Maity, Chetan H Mehta, Akhil Suresh, Usha Y Nayak, Yogendra Nayak, ","doi":"10.1016\/j.arcmed.2020.09.013","abstract":"Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) induced Novel Coronavirus Disease (COVID-19) has currently become pandemic worldwide. Though drugs like remdesivir, favipiravir, and dexamethasone found beneficial for COVID-19 management, they have limitations clinically, and vaccine development takes a long time. The researchers have reported key proteins which could act as druggable targets. Among them, the major protease M<sup>pro<\/sup> is first published, plays a prominent role in viral replication and an attractive drug-target for drug discovery. Hence, to target M<sup>pro<\/sup> and inhibit it, we accomplished the virtual screening of US-FDA approved drugs using well-known drug repurposing approach by computer-aided tools.","type":"Research","database":"PubMed","created":"2020-09-16"},{"id":1861,"name":"The SARS-CoV-2 Nucleocapsid Protein and Its Role in Viral Structure, Biological Functions, and a Potential Target for Drug or Vaccine Mitigation.","author":"Zhihua Bai, Ying Cao, Wenjun Liu, Jing Li, ","doi":"10.3390\/v13061115","abstract":"The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the world is still expanding. Thus, there is an urgent need to better understand this novel virus and find a way to control its spread. Like other coronaviruses, the nucleocapsid (N) protein is one of the most crucial structural components of SARS-CoV-2. This protein shares 90% homology with the severe acute respiratory syndrome coronavirus N protein, implying functional significance. Based on the evolutionary conservation of the N protein in coronavirus, we reviewed the currently available knowledge regarding the SARS-CoV-2 N protein in terms of structure, biological functions, and clinical application as a drug target or vaccine candidate.","type":"Review","database":"PubMed","created":"2021-06-09"},{"id":755,"name":"Aminoglycosides as potential inhibitors of SARS-CoV-2 main protease: an in silico drug repurposing study on FDA-approved antiviral and anti-infection agents","author":"Mohammad Z. Ahmed, Qamar Zia, Anzarul Haque, Ali S. Alqahtani, Omar M. Almarfadi, Saeed Banawas, Mohammed S. Alqahtani, Keshav L. Ameta, Shafiul Haque","doi":"10.1016\/j.jiph.2021.01.016","abstract":"Background\r\nThe emergence and spread of SARS-CoV-2 throughout the world has created an enormous socioeconomic impact. Although there are several promising drug candidates in clinical trials, none is available clinically. Thus, the drug repurposing approach may help to overcome the current pandemic.\r\n\r\nMethods\r\nThe main protease (Mpro) of SARS-CoV-2 is crucial for cleaving nascent polypeptide chains. Here, FDA-approved antiviral and anti-infection drugs were screened by high-throughput virtual screening (HTVS) followed by re-docking with standard-precision (SP) and extra-precision (XP) molecular docking. The most potent drug's binding was further validated by free energy calculations (Prime\/MM-GBSA) and molecular dynamics (MD) simulation.\r\n\r\nResults\r\nOut of 1397 potential drugs, 157 showed considerable affinity toward Mpro. After HTVS, SP, and XP molecular docking, four high-affinity lead drugs (Iodixanol, Amikacin, Troxerutin, and Rutin) with docking energies \u221210.629 to \u221211.776 kcal\/mol range were identified. Among them, Amikacin exhibited the lowest Prime\/MM-GBSA energy (\u221273.800 kcal\/mol). It led us to evaluate other aminoglycosides (Neomycin, Paramomycin, Gentamycin, Streptomycin, and Tobramycin) against Mpro. All aminoglycosides were bound to the substrate-binding site of Mpro and interacted with crucial residues. Altogether, Amikacin was found to be the most potent inhibitor of Mpro. MD simulations of the Amikacin-Mpro complex suggested the formation of a complex stabilized by hydrogen bonds, salt bridges, and van der Waals interactions.\r\n\r\nConclusion\r\nAminoglycosides may serve as a scaffold to design potent drug molecules against COVID-19. However, further validation by in vitro and in vivo studies is required before using aminoglycosides as an anti-COVID-19 agent.","type":"Research","database":"PubMed","created":"2021-08-05"},{"id":754,"name":"Strong Binding of Leupeptin with TMPRSS2 Protease May Be an Alternative to Camostat and Nafamostat for SARS-CoV-2 Repurposed Drug: Evaluation from Molecular Docking and Molecular Dynamics Simulations","author":"Jaganathan Ramakrishnan, Saravanan Kandasamy, Ancy Iruthayaraj, Sivanandam Magudeeswaran, Kalaiarasi Chinnasamy, Kumaradhas Poomani ","doi":"10.1007\/s12010-020-03475-8","abstract":"The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine\/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.","type":"Research","database":"PubMed","created":"2021-08-05"},{"id":753,"name":"The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro","author":"Raphael J. Eberle, Danilo S. Olivier, Marcos S. Amaral, Ian Gering, Dieter Willbold, Raghuvir K. Arni, Monika A. Coronad","doi":"10.3390\/v13050873","abstract":"Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.","type":"Research","database":"PubMed","created":"2021-07-13"},{"id":752,"name":"Identification of FDA approved drugs against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and 3-chymotrypsin-like protease (3CLpro), drug repurposing approach","author":"Zahra Molavi, Sara Razi, Seyed Amir Mirmotalebisohi, Amirjafar Adibi, Marzieh Sameni, Farshid Karami, Vahid Niazi, Zahra Niknam, Morteza Aliashrafi, Mohammad Taheri, Soudeh Ghafouri-Fard, Shabnam Jeibouei, Soodeh Mahdian, Hakimeh Zali, Mohammad Mehdi Ranjbar, Mohsen Yazdani,","doi":"10.1016\/j.biopha.2021.111544","abstract":"The RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) from SARS-CoV-2 play crucial roles in the viral life cycle and are considered the most promising targets for drug discovery against SARS-CoV-2. In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach. The number of ligands selected from the PubChem database of NCBI for screening was 1760. Ligands were energy minimized using Open Babel. The RdRp and 3CLpro protein sequences were retrieved from the NCBI database. For Homology Modeling predictions, we used the Swiss model server. Their structure was then energetically minimized using SPDB viewer software and visualized in the CHIMERA UCSF software. Molecular dockings were performed using AutoDock Vina, and candidate drugs were selected based on binding affinity (\u2206G). Hydrogen bonding and hydrophobic interactions between ligands and proteins were visualized using Ligplot and the Discovery Studio Visualizer v3.0 software. Our results showed 58 drugs against RdRp, which had binding energy of \u2212 8.5 or less, and 69 drugs to inhibit the 3CLpro enzyme with a binding energy of \u2212 8.1 or less. Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib and dihydroergotamine for 3clpro and Lapatinib, Dexasone and Relategravir for RdRp). Except for Lapatinib, other drugs-complexes were stable during MD simulation. Raltegravir, an anti-HIV drug, was observed to be the best compound against RdRp based on docking binding energy (\u2212 9.5 kcal\/mole) and MD results. According to the MD results and binding energy, dihydroergotamine is a suitable candidate for 3clpro inhibition (\u2212 9.6 kcal\/mol). These drugs were classified into several categories, including antiviral, antibacterial, anti-inflammatory, anti-allergic, cardiovascular, anticoagulant, BPH and impotence, antipsychotic, antimigraine, anticancer, and so on. The common prescription-indications for some of these medication categories appeared somewhat in line with manifestations of COVID-19. We hope that they can be beneficial for patients with certain specific symptoms of SARS-CoV-2 infection, but they can also probably inhibit viral enzymes. We recommend further experimental evaluations in vitro and in vivo on these FDA-approved drugs to assess their potential antiviral effect on SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-07-05"},{"id":751,"name":"Molecules against Covid-19: An in silico approach for drug development","author":"Rhythm Bharti, Sandeep Kumar Shukla","doi":"10.1016\/j.jnlest.2021.100095","abstract":"A large number of deaths have been caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, turning it into a serious and momentous threat to public health. This study tends to contribute to the development of effective treatment strategies through a computational approach, investigating the mechanisms in relation to the binding and subsequent inhibition of SARS-CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). Molecular docking was performed to screen six naturally occurring molecules with antineoplastic properties (Ellipticine, Ecteinascidin, Homoharringtonine, Dolastatin 10, Halichondrin, and Plicamycin). Absorption, distribution, metabolism, and excretion (ADME) investigation was also conducted to analyze the drug-like properties of these compounds. The docked results have clearly shown binding of ligands to the SARS-CoV-2 RdRp protein. Interestingly, all ligands were found to obey Lipinski\u2019s rule of five. These results provide a basis for repurposing and using molecules, derived from plants and animals, as a potential treatment for the coronavirus disease 2019 (COVID-19) infection as they could be effective therapeutics for the same.","type":"Research","database":"PMC","created":"2021-07-05"},{"id":750,"name":"Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study","author":"Ahmed Abdelaal Ahmed Mahmoud M. Alkhatip, Michail Georgakis, Lucio R. Montero Valenzuela, Mohamed Hamza, Ehab Farag, Jaqui Hodgkinson, Hisham Hosny, Ahmed M. Kamal, Mohamed Wagih, Amr Naguib, Hany Yassin, Haytham Algameel, Mohamed Elayashy, Mohamed Abdelhaq, Mohamed I. Younis, Hassan Mohamed, Mohammed Abdulshafi, Mohamed A. Elramely","doi":"10.3390\/ijms22062977","abstract":"SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at \u22128.3 kcal\/mol, followed by Zn and Ca at \u22128.0 kcal\/mol, and Fe and Mg at \u22127.9 kcal\/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn\u2013Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and\/or prophylaxis.","type":"Research","database":"PMC","created":"2021-07-05"},{"id":749,"name":"High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors","author":" Yao Zhao, Xiaoyu Du, Yinkai Duan, Xiaoyan Pan, Yifang Sun, Tian You, Lin Han, Zhenming Jin, Weijuan Shang, Jing Yu, Hangtian Guo, Qianying Liu, Yan Wu, Chao Peng, Jun Wang, Chenghao Zhu, Xiuna Yang, Kailin Yang, Ying Lei, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Lei Sun, Leike Zhang, Zihe Rao, Haitao Yang","doi":"10.1007\/s13238-021-00836-9","abstract":"A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 \u03bcmol\/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol\/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three \u201chot\u201d spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.","type":"Research","database":"PMC","created":"2021-07-05"},{"id":748,"name":"A SARS-CoV-2 cytopathicity dataset generated by high-content screening of a large drug repurposing collection","author":"Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Oliver Keminer, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek ","doi":"10.1038\/s41597-021-00848-4","abstract":"SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic, in which acute respiratory infections are associated with high socio-economic burden. We applied high-content screening to a well-defined collection of 5632 compounds including 3488 that have undergone previous clinical investigations across 600 indications. The compounds were screened by microscopy for their ability to inhibit SARS-CoV-2 cytopathicity in the human epithelial colorectal adenocarcinoma cell line, Caco-2. The primary screen identified 258 hits that inhibited cytopathicity by more than 75%, most of which were not previously known to be active against SARS-CoV-2 in vitro. These compounds were tested in an eight-point dose response screen using the same image-based cytopathicity readout. For the 67 most active molecules, cytotoxicity data were generated to confirm activity against SARS-CoV-2. We verified the ability of known inhibitors camostat, nafamostat, lopinavir, mefloquine, papaverine and cetylpyridinium to reduce the cytopathic effects of SARS-CoV-2, providing confidence in the validity of the assay. The high-content screening data are suitable for reanalysis across numerous drug classes and indications and may yield additional insights into SARS-CoV-2 mechanisms and potential therapeutic strategies.","type":"Other","database":"PubMed","created":"2021-07-05"},{"id":747,"name":"High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV-2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity","author":" Ryan Choi,Mowei Zhou,Roger Shek,Jesse W. Wilson,Logan Tillery,Justin K. Craig,Indraneel A. Salukhe,Sarah E. Hickson,Neeraj Kumar,Rhema M. James,Garry W. Buchko,Ruilian Wu,Sydney Huff,Tu-Trinh Nguyen,Brett L. Hurst,Sara Cherry,Lynn K. Barrett,Jennifer L. Hyde,Wesley C. Van Voorhis","doi":"10.1371\/journal.pone.0250019","abstract":"SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1\u201320 \u03bcM range in vitro. Furthermore, Exebryl-1, a \u00df-amyloid anti-aggregation molecule for Alzheimer\u2019s therapy, was shown to have antiviral activity between 10 to 66 \u03bcM, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.","type":"Research","database":"PubMed","created":"2021-07-05"},{"id":746,"name":"Drug repurposing approach to fight COVID-19","author":"Thakur Uttam Singh, Subhashree Parida, Madhu Cholenahalli Lingaraju, Manickam Kesavan, Dinesh Kumar, Raj Kumar Singh ","doi":"10.1007\/s43440-020-00155-6","abstract":"Currently, there are no treatment options available for the deadly contagious disease, coronavirus disease 2019 (COVID-19). Drug repurposing is a process of identifying new uses for approved or investigational drugs and it is considered as a very effective strategy for drug discovery as it involves less time and cost to find a therapeutic agent in comparison to the de novo drug discovery process. The present review will focus on the repurposing efficacy of the currently used drugs against COVID-19 and their mechanisms of action, pharmacokinetics, dosing, safety, and their future perspective. Relevant articles with experimental studies conducted in-silico, in-vitro, in-vivo, clinical trials in humans, case reports, and news archives were selected for the review. Number of drugs such as remdesivir, favipiravir, ribavirin, lopinavir, ritonavir, darunavir, arbidol, chloroquine, hydroxychloroquine, tocilizumab and interferons have shown inhibitory effects against the SARS-CoV2 in-vitro as well as in clinical conditions. These drugs either act through virus-related targets such as RNA genome, polypeptide packing and uptake pathways or target host-related pathways involving angiotensin-converting enzyme-2 (ACE2) receptors and inflammatory pathways. Using the basic knowledge of viral pathogenesis and pharmacodynamics of drugs as well as using computational tools, many drugs are currently in pipeline to be repurposed. In the current scenario, repositioning of the drugs could be considered the new avenue for the treatment of COVID-19.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":745,"name":"Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19","author":"Amjad Husain, Siddappa N.Byrareddy","doi":"10.1016\/j.cbi.2020.109282","abstract":"The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of pro-inflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19\/SARS-CoV-2 infection.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":744,"name":"Comprehensive analysis of drugs to treat SARS\u2011CoV\u20112 infection: Mechanistic insights into current COVID\u201119 therapies (Review)","author":"GeoMihai Nitulescu, Horia Paunescu, Sterghios A. Moschos, Dimitrios Petrakis, Georgiana Nitulescu, George Nicolae Daniel Ion, Demetrios A. Spandidos, Taxiarchis Konstantinos Nikolouzakis, Nikolaos Drakoulis, Aristidis Tsatsakis","doi":"10.3892\/ijmm.2020.4608","abstract":"The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS\u2011CoV\u20112) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID\u201119). This work represents an exhaustive and critical review of all available data on potential treatments for COVID\u201119, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":743,"name":"Literature-based review of the drugs used for the treatment of COVID-19","author":"Meda Venkatasubbaiah, P.Dwarakanadha Reddy, Suggala V.Satyanarayana","doi":"10.1016\/j.cmrp.2020.05.013","abstract":"COVID-19 is primarily a respiratory disease caused by a newly discovered SARS-CoV-2 virus and identified in the city of Wuhan, China in December 2019. WHO has declared this disease as a pandemic, and warned other countries. Presently this has affected 216 countries, areas or territories worldwide, spreading of this disease is very fast in USA, Brazil, and Russia than in the country of its origin, China. Like other coronaviruses, this may develop respiratory tract infections in the patients range from mild to fatal illness like pneumonia and acute respiratory distress syndrome (ARDS). As of now, no effective drug, vaccine, or any procedure is available and experiments are underway. However, empirical therapy is being followed to manage and save the lives of the patients. There is a need for pharmacological alternatives to combat this deadly virus and its complications. Based on the previous experiences with similar coronavirus management and present preliminary data from uncontrolled studies, drugs like chloroquine, hydroxychloroquine, remdesivir, lopinavir\/ritonavir, and favipiravir have been recommended by the researchers to manage COVID-19. This review had assessed the potential mechanisms, safety profile, availability and cost of these drugs. This review concludes that the drugs mentioned above are having different properties and act differently in combating the COVID-19 viruses. Instead of single drug, combination of antivirals with different mechanism of action may be more effective and at the same time their adverse events should not be underestimated.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":742,"name":"Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply","author":" Chris De Savi, David L. Hughes, Lisbet Kvaerno","doi":"10.1021\/acs.oprd.0c00233","abstract":"The outbreak of the COVID-19 pandemic has spurred an intense global effort to repurpose existing approved drugs for its treatment. In this review, we highlight the development of seven small-molecule drugs that are currently being assessed in clinical trials for the treatment of COVID-19. Three sections are presented for each drug: (1) history, mechanism of action, and status of clinical trials; (2) scalable synthetic routes and final forms; and (3) outlook for supply should clinical trials show treatment efficacy. A brief overview of diagnostic testing and vaccine development is also presented.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":741,"name":"Chloroquine: A Potential Drug in the COVID-19 Scenario","author":"Ranjana Singh, Viji Vijayan ","doi":"10.1007\/s41403-020-00114-w","abstract":"Today, the whole world is fighting a public health emergency called \u2018COVID-19\u2019 caused by a new infectious virus called SARS-CoV2. Any person can catch COVID-19 from an infected person via aerosol droplets when the person coughs, sneezes, or speaks. To limit such a transmission, World Health Organization (WHO) has recommended people to wear masks and physically distance themselves by staying at least 1 m (3 feet) away from others. As aerosol droplets (by cough or sneeze) land on objects and surfaces around the person such as tables, doorknobs and handrails, and remain active on these surfaces for hours to days, people are advised to use soaps for at least 20 s. and alcohol-based sanitizers as well. As the public made efforts, clinicians and researchers investigated and found that drugs which were initially used to treat other diseases may work as a treatment option for COVID-19. One of those drugs was Chloroquine and its related derivative called hydroxychloroquine. In this review article, we have systematically searched for details of COVID-19 pandemic till May 2020 and assembled few data pertaining to (i) Corona viruses; (ii) SARS-CoV2, the virus that causes COVID-19\u2019 and (iii) How chloroquine and hydroxychloroquine mediates anti-viral effect in both prophylactic and therapeutic setting. These data have been acquired mostly from PubMed and websites of WHO and Indian Council for Medical Research (ICMR). We did a systematic search and found that the properties of chloroquine are very much essential for the COVID-19 scenario. We also bring to you some evidence that the anti-lysosomal activity of chloroquine may be increased by botanicals like betulinic acid.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":740,"name":"Systematic review of registered trials of Hydroxychloroquine prophylaxis for COVID-19 health-care workers at the first third of 2020","author":"Anne-Lise Bienvenu, Aileen M.Marty, Malcolm K.Jones, Stephane Picot","doi":"10.1016\/j.onehlt.2020.100141","abstract":"In the absence of a vaccine the medical and scientific community is looking intensely at utilizing a pre or post exposure drug that could decrease viremia. The search for a medication that could reduce risk of serious disease, and ideally of any manifestation of disease from SARS-CoV2, and of asymptomatic shedding of SARS-CoV2 is of urgent interest. Repurposing existing pharmaceuticals is among the approaches to achieve these ends. We performed a systematic review of all interventional studies registered in ClinicalTrials.gov with a focus on one repurposed drug, Hydroxychloroquine (HCQ). The detailed analysis of these studies, some of them already recruiting, provide an overall picture of HCQ use as a COVID-19 prophylaxis around the world. Among the included studies, all but three were randomized and parallel and most of them (74%, 23\/31) were double-blinded to quadruple-blinded studies. We found a great diversity in dosing and nearly all the possible scientifically reasonable regimens are under evaluation. This diversity offers benefits as well as challenges. Importantly, the final analysis of these trials should be done through an extensive reading of the results in regard to the clinical design, it will be crucial to carefully read and evaluate the results of each study in regards to the clinical design rather than quickly glancing a 140 characters-based social media message announcing the failure or success of a drug against a disease.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":739,"name":"COVID 19 therapies and anti-cancer drugs: A systematic review of recent literature","author":"Giuseppe Di Lorenzoab, Rossella Di Trolioc, Zisis Kozlakidisd, Giuseppina Bustoa, Concetta Ingenitoa, Luciana Buonerbaa, Claudia Ferraraa, Annamaria Libroiaa, Gianluca Ragonea, Concetta dello Ioioa, Beatrice Savastanoa, Mario Polverinoa, Ferdinando De Falcoa, Simona Iaccarinoa, Emilio Leoa","doi":"10.1016\/j.critrevonc.2020.102991","abstract":"Background\r\nIt is reasonable to think that cancer patients undergoing chemotherapy, targeted therapy or immunotherapy could have a more aggressive course if positive for Coronavirus disease CoV-2 (COVID- 19).\r\n\r\nMethods\r\nWe conducted a literature review on https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/, https:\/\/scholar.google.com, www.arxiv.org, www.biorxiv.org, of all articles published using the keywords COVID-19 therapy or treatment and cancer until May 2, 2020. A total of 205 articles were identified and 53 were included in this review.\r\n\r\nResults\r\nWe describe the ongoing COVID-19 therapies that should be known by oncologists and highlight the potential interactions with antineoplastic drugs, commonly used in clinical practice. The main drug interactions were found with tocilizumab, ruxolitinib and colchicine. Conclusions. The literature provides an inconclusive picture on potential preferred treatments for COVID-19 and their interactions with antineoplastic agents. Future clinical trials are needed to better understand the interactions between different drugs in the context of COVID-19 pandemic.\r\n\r\n","type":"Review","database":"PMC","created":"2021-06-21"},{"id":738,"name":"Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak","author":"Zheng Yao Low, Isra Ahmad Farouk, Sunil Kumar Lal","doi":"10.3390\/v12091058","abstract":"Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing\u2019s syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":737,"name":"COVID-19: Current Developments and Further Opportunities in Drug Delivery and Therapeutics","author":"Saman Zafar, Muhammad Sohail Arshad, Sameen Fatima, Amna Ali, Aliyah Zaman, Elshaimaa Sayed, Ming-Wei Chang, Zeeshan Ahmad","doi":"10.3390\/pharmaceutics12100945","abstract":"SARS-CoV-2 has affected people from all age groups, races and ethnicities. Given that many infected individuals are asymptomatic, they transmit the disease to others unknowingly, which has resulted in the spread of infection at an alarming rate. This review aims to provide an overview of the pathophysiology, preventive measures to reduce the disease spread, therapies currently in use, an update on vaccine development and opportunities for vaccine delivery. The World Health Organization has advised several precautions including social distancing, hand washing and the use of PPE including gloves and face masks for minimizing the spread of SARS-CoV-2 infection. At present, several antiviral therapies previously approved for other infections are being repositioned to study their efficacy against SARS-CoV-2. In addition, some medicines (i.e., remdesivir, chloroquine, hydroxychloroquine) have received emergency use authorisation from the FDA. Plasma therapy has also been authorised for emergency use for the treatment of COVID-19 on a smaller scale. However, no vaccine has been approved so far against this virus. Nevertheless, several potential vaccine targets have been reported, and development of different types of vaccines including DNA, mRNA, viral vector, inactivated, subunit and vaccine-like particles is in process. It is concluded that a suitable candidate delivered through an advanced drug delivery approach would effectively boost the immune system against this coronavirus.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":736,"name":"The Current Recommended Drugs and Strategies for the Treatment of Coronavirus Disease (COVID-19)","author":"Sheikhpour M","doi":"10.2147\/TCRM.S262936","abstract":"Background: The coronavirus 2019 (COVID-19) has been known as a pandemic disease by the World Health Organization (WHO) worldwide. The drugs currently used for treatment of COVID-19 are often selected and tested based on their effectiveness in other diseases such as influenza and AIDS and their major identified targets are viral protease, host cell produced protease, viral RNA polymerase, and the interaction site of viral protein with host cell receptors. Until now, there are no approved therapeutic drugs for definitive treatment of this dangerous disease.\r\nMethods: In this article, all of the documentary information, such as clinical trials, original research and reviews, government\u2019s database, and treatment guidelines, were reviewed critically and comprehensively. Moreover, it was attempted to present the most common and effective drugs and strategies, to suggest the possible treatment way of COVID19 by focusing on the body\u2019s defense mechanism against pathogens.\r\nResults: Antiviral drugs and immune-modulatory agents with the traditional medicines using the natural compound are usual accessible treatments. Accordingly, they have better beneficence due to the large existence studies, long time follow-ups, proximity to the natural system, and the normal physiological routine of the pathogen and host interactions. Besides, the serotonergic and dopaminergic pathways are considered as attractive targets to treat human immune, infectious, and cancerous diseases. Fluoxetine, as a host-targeted small molecule with immunomodulatory action, may be known as effective drug for treatment and prevention of COVID19 disease, in combination with antiviral drugs and natural compounds.\r\nConclusion: Co-administration of fluoxetine in the treatment of COVID19 could be considered due to the possibility of its interaction with ACE2 receptors, immune-modulatory function, and a proper immune response at the right time. Fluoxetine plays a beneficial role in reducing stress due to fear of infecting by COVID19 or worsening the disease and psychological support for the affected patients.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":735,"name":"Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations","author":"Anastasiia I. Petushkova, Andrey A. Zamyatnin","doi":"10.3390\/ph13100277","abstract":"Papain-like proteases (PLpro) of coronaviruses (CoVs) support viral reproduction and suppress the immune response of the host, which makes CoV PLpro perspective pharmaceutical targets. Their inhibition could both prevent viral replication and boost the immune system of the host, leading to the speedy recovery of the patient. Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third CoV outbreak in the last 20 years. Frequent mutations of the viral genome likely lead to the emergence of more CoVs. Inhibitors for CoV PLpro can be broad-spectrum and can diminish present and prevent future CoV outbreaks as PLpro from different CoVs have conservative structures. Several inhibitors have been developed to withstand SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). This review summarizes the structural features of CoV PLpro, the inhibitors that have been identified over the last 20 years, and the compounds that have the potential to become novel effective therapeutics against CoVs in the near future.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":734,"name":"Combating COVID-19: The role of drug repurposing and medicinal plants","author":"Shah A.Khan, K.Al-Balushi","doi":"10.1016\/j.jiph.2020.10.012","abstract":"Background\r\nA novel corona virus-2 disease has spread to 213 countries and territories across the globe. The corona pandemic has claimed more than 548,934 deaths worldwide till the evening of 8th of July 2020 and the number of confirmed cases is increasing at an alarming rate. Therefore, there is an urgent need to find a treatment or a vaccine for COVID-19 at the earliest. The aim of this mini-review is to give an overview of identified repurposed anti-COVID-19 drugs which are currently under clinical trials.\r\n\r\nMethods\r\nA thorough literature survey was done to retrieve relevant information using various web based search engines such as Google, Google scholar, and various other electronic research databases such as PubMed, Medline, MeSh etc. The findings of the recently published articles, clinical trials, COVID-19 update by World Health Organization etc., and the opinion of the authors is summarized in this brief review. The antiviral medicinal plants were identified based on their use in Chinese\/Indian indigenous systems of medicine, traditional use, published scientific phytochemical studies and\/or their effectiveness against upper respiratory infections, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS).\r\n\r\nResults\r\nThe disease is just over six months old and effective prophylactic or therapeutic agents are yet to be developed for COVID-19. Thus, in the absence of an effective therapy, scientific community has rationally considered the drug repurposing approach for the development of anti COVID-19 drugs. Various studies and clinical trials involving antimalarial drugs, anti-HIV drugs, anti-hepatitis drugs, anti-parasitic drug, anti-inflammatory drugs, the combination of antimalarial and macrolide antibiotic and few other molecules identified through drug repurposing are currently underway to combat COVID-19. Due emphasis is also given to develop novel corona vaccines for the prophylaxis and to identify drugs for adjunct\/supportive therapy. Several medicinal plants along with their major phytochemicals exhibiting antiviral activity are identified for further exploration. It is anticipated that these natural products might also play an important role in combating COVID-19.\r\n\r\nConclusions\r\nUse of drug repurposing strategy to develop anti COVID-19 drugs and exploring antiviral medicinal plants as adjunct or supportive therapy appears to be a viable option. Therefore, it is the need of the hour to work in parallel on different strategies such as genetic engineering, in silico approach, herbal remedies and drug repositioning to achieve the common goal of finding a safe and effective treatment for COVID-19 at the earliest.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":733,"name":"Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine","author":"Babayeva M, Loewy Z","doi":"10.2147\/PGPM.S275964","abstract":"Background: A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019\u2013 20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking.\r\nMethods: A review of the literature was performed using Medline\/PubMed\/Embase database. A variety of keywords were employed in keyword\/title\/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles.\r\nResults: A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity.\r\nConclusion: Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":732,"name":"Repurposed Drugs, Molecular Vaccines, Immune-Modulators, and Nanotherapeutics to Treat and Prevent COVID-19 Associated with SARS-CoV-2, a Deadly Nanovector","author":"Taru Dube, Amrito Ghosh, Jibanananda Mishra, Uday B. Kompella, Jiban Jyoti Panda","doi":"10.1002\/adtp.202000172","abstract":"The deadly pandemic, coronavirus disease 2019 (COVID-19), caused due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has paralyzed the world. Although significant methodological advances have been made in the field of viral detection\/diagnosis with 251 in vitro diagnostic tests receiving emergency use approval by the US-FDA, little progress has been made in identifying curative or preventive therapies. This review discusses the current trends and potential future approaches for developing COVID-19 therapeutics, including repurposed drugs, vaccine candidates, immune-modulators, convalescent plasma therapy, and antiviral nanoparticles\/nanovaccines\/combinatorial nanotherapeutics to surmount the pandemic viral strain. Many potent therapeutic candidates emerging via drug-repurposing could significantly reduce the cost and duration of anti-COVID-19 drug development. Gene\/protein-based vaccine candidates that could elicit both humoral and cell-based immunity would be on the frontlines to prevent the disease. Many emerging nanotechnology-based interventions will be critical in the fight against the deadly virus by facilitating early detection and enabling target oriented multidrug therapeutics. The therapeutic candidates discussed in this article include remdesivir, dexamethasone, hydroxychloroquine, favilavir, lopinavir\/ritonavir, antibody therapeutics like gimsilumab and TJM2, anti-viral nanoparticles, and nanoparticle-based DNA and mRNA vaccines.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":731,"name":"Lopinavir\/ritonavir: Repurposing an old drug for HIV infection in COVID-19 treatment","author":"PaolaMagro, Isabella Zanella, Marta Pescarolo, Francesco Castelli, Eugenia Quiros-Roldand","doi":"10.1016\/j.bj.2020.11.005","abstract":"Currently, there is no specific antiviral treatment for COVID-19. However, drugs previously developed to treat other viral infections are being tested to verify if they might also be effective against SARS-CoV-2, the virus that causes COVID-19. Twenty years ago, the F.D.A. approved Lopinavir\/ritonavir (LPV\/r) to treat HIV infection. LPV and ritonavir were initially purposed to inhibit 3-chymotrypsin-like protease (3CLpro) of SARS-CoV and MERS-CoV and preliminary promising data on its efficacy for treating people infected with those viruses were available. Therefore, due to the high genetic similarities among those viruses and SARS-CoV-2, early during COVID-19 pandemic LPV\/r was also proposed as one emergency treatment. We reviewed data from the literature about LPV\/r treatment and SARS-CoV-2 infection, mainly focused on the efficacy and safety of this drugs for COVID-19 treatment. We can conclude that although up to date no clear benefit has been observed with the LPV\/r treatment beyond standard care, its efficacy against SARS-COV-2 infection deserves further evaluations, particularly during the very early phase of the disease.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":730,"name":"Natural and Synthetic Drugs as Potential Treatment for Coronavirus Disease 2019 (COVID-2019)","author":"Saba Farooq, Zainab Ngaini ","doi":"10.1007\/s42250-020-00203-x","abstract":"Coronavirus disease 2019 (COVID-19) has become a global pandemic in a short period, where a tragically large number of human lives being lost. It is an infectious pandemic that recently infected more than two hundred countries in the world. Many potential treatments have been introduced, which are considered potent antiviral drugs and commonly reported as herbal or traditional and medicinal treatments. A variety of bioactive metabolites extracts from natural herbal have been reported for coronaviruses with some effective results. Food and Drug Administration (FDA) has approved numerous drugs to be introduced against COVID-19, which commercially available as antiviral drugs and vaccines. In this study, a comprehensive review is discussed on the potential antiviral remedies based on natural and synthetic drugs. This review highlighted the potential remedies of COVID-19 which successfully applied to patients with high cytopathic inhibition potency for cell-to-cell spread and replication of coronavirus.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":729,"name":"Challenges for Drug Repurposing in the COVID-19 Pandemic Era","author":"Janet Sultana, Salvatore Crisafulli, Flic Gabbay, Elizabeth Lynn, Saad Shakir, Gianluca Trifir\u00f2","doi":"10.3389\/fphar.2020.588654","abstract":"The coronavirus disease (COVID-19) pandemic has affected an estimated 16 million persons and caused 0.6 million deaths worldwide by September 2020. The pandemic has led to a rush to repurpose existing drugs, although the underlying evidence base is of variable quality. The improving knowledge of the virology and clinical presentation of COVID-19 is leading to a broadening pool of potential pharmacological targets. The aim of this review is to describe regulatory and pharmacological aspects of drug repurposing and to identify drugs proposed for repurposing in COVID-19 based on registered clinical trials, discussing the evidence to support their use in the treatment of this disease. The challenges of the correct interpretation of existing pre-clinical\/clinical evidence as well as the generation of new evidence concerning drug repurposing in COVID-19 will also be discussed.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":728,"name":"Drug Repurposing Approaches to Combating Viral Infections","author":"Jay Trivedi, Mahesh Mohan, Siddappa N. Byrareddy","doi":"10.3390\/jcm9113777","abstract":"Development of novel antiviral molecules from the beginning costs an average of $350 million to $2 billion per drug, and the journey from the laboratory to the clinic takes about 10\u201315 years. Utilization of drug repurposing approaches has generated substantial interest in order to overcome these drawbacks. A drastic reduction in the failure rate, which otherwise is ~92%, is achieved with the drug repurposing approach. The recent exploration of the drug repurposing approach to combat the COVID-19 pandemic has further validated the fact that it is more beneficial to reinvestigate the in-practice drugs for a new application instead of designing novel drugs. The first successful example of drug repurposing is zidovudine (AZT), which was developed as an anti-cancer agent in the 1960s and was later approved by the US FDA as an anti-HIV therapeutic drug in the late 1980s after fast track clinical trials. Since that time, the drug repurposing approach has been successfully utilized to develop effective therapeutic strategies against a plethora of diseases. Hence, an extensive application of the drug repurposing approach will not only help to fight the current pandemics more efficiently but also predict and prepare for newly emerging viral infections. In this review, we discuss in detail the drug repurposing approach and its advancements related to viral infections such as Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).","type":"Review","database":"PMC","created":"2021-06-21"},{"id":727,"name":"Impact of repurposed drugs on the symptomatic COVID-19 patients","author":"Iqbal Hussain, Afzal Hussain, Mohamed F.Alajmi, Tabish Rehman, Samira Amir","doi":"10.1016\/j.jiph.2020.11.009","abstract":"An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus capable of causing coronavirus disease 2019 (COVID-19), was declared as a global public health emergency on January 30, 2020, by the World Health Organization. In this devastating situation, precautionary measures, early diagnosis, and repurposed drugs appear to be timely and decisive factors by which to handle this problem until the discovery of an effective, dedicated vaccine or medicine is made. Currently, some researchers and clinicians have claimed evidence exists in favor of the use of some antimalarial drugs (chloroquine, hydroxychloroquine) antiviral drugs (remdesivir, favipiravir, lopinavir, ritonavir, umifenovir) vitamins, traditional Chinese medicines, and herbal medicines against SARS-CoV-2 infection. Based on the available literature, this review article sought to highlight the current understanding of the origin, transmission, diagnosis, precautionary measures, infection and drug action mechanisms, therapeutic role, and toxicities of targeted drugs for the prevention and cure of COVID-19. This review may be useful for developing further strategies as a blueprint and understanding the mentioned drugs\u2019 mechanisms to elucidate the possible target of action by which to successfully freeze the replication of the SARS-CoV-2 virus.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":726,"name":"Phytochemicals against SARS-CoV as potential drug leads","author":"Shasank Sekhar Swaina, Sujogya Kumar Panda, Walter Luyten","doi":"10.1016\/j.bj.2020.12.002","abstract":"The newly emerged SARS-CoV-2 strains from the coronavirus (CoV) family is causing one of the most disruptive pandemics of the past century. Developing antiviral drugs is a challenge for the scientific community and pharmaceutical industry. Given the health emergency, repurposing of existing antiviral, antiinflammatory or antimalarial drugs is an attractive option for controlling SARS-CoV-2 with drugs. However, phytochemicals selected based on ethnomedicinal information as well as in vitro antiviral studies could be promising as well. Here, we summarise the phytochemicals with reported anti-CoV activity, and further analyzed them computationally to accelerate validation for drug development against SARS-CoV-2. This systematic review started from the most potent phytocompounds (IC50 in \u03bcM) against SARS-CoV, followed by a cluster analysis to locate the most suitable lead(s). The advanced molecular docking used the crystallography structure of SARS-CoV-2-cysteine-like protease (SARS-CoV-2-3CLpro) as a target. In total, seventy-eight phytochemicals with anti-CoV activity against different strains in cellular assays, were selected for this computational study, and compared with two existing repurposed FDA-approved drugs: lopinavir and ritonavir. This review brings insights in the potential application of phytochemicals and their derivatives, which could guide researchers to develop safe drugs against SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":725,"name":"COVID-19: inflammatory responses, structure-based drug design and potential therapeutics","author":"Neetu Tripathi, Neeraj Tripathi, Manoj Kumar Goshisht ","doi":"10.1007\/s11030-020-10176-1","abstract":"The COVID-19 pandemic caused by SARS-CoV-2 is responsible for the global health emergency. Here, we explore the diverse mechanisms of SARS-CoV-induced inflammation. We presume that SARS-CoV-2 likely contributes analogous inflammatory responses. Possible therapeutic mechanisms for reducing SARS-CoV-2-mediated inflammatory responses comprise FcR inactivation. Currently, there is no specific remedy available against the SARS-CoV-2. Consequently, recognizing efficacious antiviral leads to combat the virus is crucially desired. The coronavirus (CoV) main protease (Mpro also called 3CLpro), which plays an indispensable role in viral replication and transcription, is an interesting target for drug design. This review compiles the latest advances in biological and structural research, along with development of inhibitors targeting CoV Mpros. It is anticipated that inhibitors targeting CoV Mpros could be advanced into wide-spectrum antiviral drugs in case of COVID-19 and other CoV-related diseases. The crystal structural and docking results have shown that Ebselen, N3, TDZD-8 and \u03b1-ketoamide (13b) inhibitors can bind to the substrate-binding pocket of COVID-19 Mpro. \u03b1-ketoamide-based inhibitor 13b inhibits the replication of SARS-CoV-2 in human Calu3 lung cells. Quantitative real-time RT-PCR (qRT-PCR) showed that the treatment with Ebselen, TDZD-8 and N3 reduced the amounts of SARS-CoV-2, respectively, 20.3-, 10.19- and 8.4-fold compared to the treatment in the absence of inhibitor. Moreover, repurposing of already present drugs to treat COVID-19 serves as one of the competent and economic therapeutic strategies. Several anti-malarial, anti-HIV and anti-inflammatory drugs as mentioned in Table 2 were found effective for the COVID-19 treatment. Further, hydroxychloroquine (HCQ) was found more potent than chloroquine (CQ) in inhibiting SARS-CoV-2 in vitro. Furthermore, convalescent plasma from patients who have recuperated from viral infections can be employed as a therapy without the appearance of severe adverse events. Hence, it might be valuable to examine the safety and efficacy of convalescent plasma transfusion in SARS-CoV-2-infected patients.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":724,"name":"Drug Repurposing for Prevention and Treatment of COVID-19: A Clinical Landscape","author":"Shahadat Hossain, Ithmam Hami, Sad Salabi Sawrav, Fazley Rabbi, Otun Saha, Newaz Mohammed Bahadur, Md. Mizanur Rahaman","doi":"10.15190\/d.2020.18","abstract":"SARS-CoV-2, the novel coronavirus strain responsible for the current pandemic of COVID-19, has rendered the entire humanity suffering. Several months have passed since the pandemic has struck. However, the world is still looking for an effective treatment plan to battle the viral infection. The first vaccine just received emergency approval in December 2020 for use in USA and UK. These are excellent news, however, the worldwide distribution of such vaccine, the possibility of virus mutation and the lack of data regarding the long-term effects of such vaccines are a significant concern. In addition, although remdesivir was recently approved by the FDA to be used as a clinical drug against COVID-19, it hasn\u2019t stood out yet as a proven form of therapeutics. Such inability to produce a novel therapy has caused enough inconveniences for the affected people worldwide. Repurposing the already available drugs to fight against the virus seems to be a reasonable option amidst such uncertainty. Given the vast collection of potential treatment candidates to be explored against COVID-19, there is a decent chance that a success in this regard will serve the intermediary purpose of clinically treating the infection until a COVID-19 vaccine is widely distributed worldwide and will be able to treat COVID-19 patients that do not adequately respond to vaccines. Such treatments may prove very useful in future coronavirus outbreaks too. Proper research into these repurposing treatments may yield a certain insight into the field of novel treatment production as well. This review study accumulates a relevant set of information about drugs and vaccines against COVID-19, in terms of their repurposing properties and the specific phases of clinical trials they are undergoing across the world.  A potential timeline is also suggested to estimate when an effective result can be expected from the ongoing clinical trials for a better anticipation of the drug landscape. This study will hopefully help accelerate investment of resources into development and discovery of drugs and vaccines against the infection.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":723,"name":"Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?","author":"Jos\u00e9 Miguel Vela","doi":"10.3389\/fphar.2020.582310","abstract":"Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and\/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.","type":"Research","database":"PMC","created":"2021-06-21"},{"id":722,"name":"COVID-19 treatment options: a difficult journey between failed attempts and experimental drugs","author":"Alessandra Bartoli, Filippo Gabrielli, Tatiana Alicandro, Fabio Nascimbeni, Pietro Andreone ","doi":"10.1007\/s11739-020-02569-9","abstract":"Since its outbreak in China in December 2019 a novel Coronavirus, named SARS-CoV-2, has spread worldwide causing many cases of severe pneumonia, referred to as COVID-19 disease, leading the World Health Organization to declare a pandemic emergency in March 2020. Up to now, no specific therapy against COVID-19 disease exists. This paper aims to review COVID-19 treatment options currently under investigation. We divided the studied drugs into three categories (antiviral, immunomodulatory and other drugs). For each molecule, we discussed the putative mechanisms by which the drug may act against SARS-CoV-2 or may affect COVID-19 pathogenesis and the main clinical studies performed so far. The published clinical studies suffer from methodological limitations due to the emergency setting in which they have been conducted. Nevertheless, it seems that the timing of administration of the diverse categories of drugs is crucial in determining clinical efficacy. Antiviral drugs, in particular Remdesivir, should be administered soon after symptoms onset, in the viraemic phase of the disease; whereas, immunomodulatory agents, such as tocilizumab, anakinra and steroids, may have better results if administered in pneumonia\/hyperinflammatory phases. Low-molecular-weight heparin may also have a role when facing COVID-19-related coagulopathy. Up to now, treatment choices have been inferred from the experience with other coronaviruses or viral infection outbreaks. Hopefully, in the near future, new treatment strategies will be available thanks to increased knowledge on SARS-CoV2 virus and COVID-19 pathogenesis. In the meanwhile, further well-designed clinical trials are urgently needed to establish a standard of care in COVID-19 disease.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":721,"name":"Plant-Based Drugs and Vaccines for COVID-19","author":"Nasir Mahmood, Sarah Bushra Nasir, Kathleen Hefferon","doi":"10.3390\/vaccines9010015","abstract":"The coronavirus SARS-CoV-2 has turned our own health and the world economy upside down. While several vaccine candidates are currently under development, antivirals with the potential to limit virus transmission or block infection are also being explored. Plant production platforms are being used to generate vaccines and antiviral proteins inexpensively and at mass scale. The following review discusses the biology and origins of the current coronavirus pandemic, and describes some of the conventional, synthetic, and plant-based approaches to address the challenge that it presents to our way of life.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":720,"name":"Exploring algae and cyanobacteria as a promising natural source of antiviral drug against SARS-CoV-2","author":"Neha Sami, Rakhshan Ahmad, Tasneem Fatma","doi":"10.1016\/j.bj.2020.11.014","abstract":"The present outburst of coronavirus-associated (SARS-CoV-2) acute respiratory disease coronavirus disease 19 (COVID-19) in December 2019 in Wuhan, China is the third recognised spill over due to the zoonotic transmission. SARS-CoVs are about 29.7 kb positive, single stranded (ss) RNA viruses that are considered as zoonotic pathogens, bat being their natural reservoirs and also shows transmission within humans. The rapidly increasing COVID-19 cases and need of best and efficient drug\/vaccine\/strategy to counteract the virus entry and its pathogenesis has made it a Herculean challenge for scientists. Synthetic drugs associated complications has attracted scientific attention for natural product-based drugs. Chemo-diversity of algae and cyanobacteria offers a novel approach and can be recognized as a relevant source for developing a future natural \u201cantiviral drug\u201d. The aim of this review is to highlight important features of SARS-CoV-2\/COVID-19 and the antiviral compounds recognized in algae and cyanobacteria, with their mechanisms of actions. Algae possess both immunity improving capacity and suppresses many viruses. Thus, they can be recommended as a preventive and curative remedy against SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":719,"name":"Antiviral drugs against severe acute respiratory syndrome coronavirus 2 infection triggering the coronavirus disease-19 pandemic","author":"Rashed Noor","doi":"10.4103\/tcmj.tcmj_100_20","abstract":"So far, lots of analyses have been conducted to invent the appropriate therapeutic targets for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The category and the strategies for treating the virus are described in this review together with mentioning some specific drugs. Of them, saikosaponin possesses affinity of the drug toward nonstructural protein 15 and the spike glycoprotein of the SARS-CoV-2. The nucleotide inhibitors such as sofosbuvir, ribavirin, galidesivir, remdesivir, favipiravir, cefuroxime, tenofovir, and hydroxychloroquine (HCHL), setrobuvir, YAK, and IDX-184 were found to be effective in binding to SARS-CoV-2 RNA-dependent RNA polymerase. From the antimalarial and anti-inflammatory category, chloroquine and its derivative HCHL have already been approved by the U.S. Food and Drug Administration for emergency treatment of SARS-CoV-2 infection. The other drugs such as favipiravir and lopinavir\/ritonavir under the antiviral category, the angiotensin-converting enzyme 2 (the renin-angiotensin system inhibitors), remdesivir (RNA polymerase inhibitor) from antiviral category, cepharanthine from anti-inflammatory category, etc., have been pointed based on the previous literature published. Besides, the assessment of the drug repositioning candidates with the related targets is also significant for the viral mitigation.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":718,"name":"Human cell receptors: potential drug targets to combat COVID-19","author":"Pawan Kumar Raghav, Keerthana Kalyanaraman, Dinesh Kumar ","doi":"10.1007\/s00726-021-02991-z","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-\u03b1 subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":717,"name":"Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase","author":" Esen Sokullu, Maxime Pinard, Marie-Soleil Gauthier, Benoit Coulombe","doi":"10.1080\/17460441.2021.1909566","abstract":"Introduction: The COVID-19 pandemic originated from the emergence of anovel coronavirus, SARS-CoV-2, which has been intensively studied since its discovery in order to generate the knowledge necessary to accelerate the development of vaccines and antivirals. Of note, many researchers believe there is great potential in systematically identifying host interactors of viral factors already targeted by existing drugs.\r\n\r\nAreas Covered: Herein, the authors discuss in detail the only available large-scale systematic study of the SARS-CoV-2-host protein\u2013protein interaction network. More specifically, the authors review the literature on two key SARS-CoV-2 drug targets, the Spike surface glycoprotein, and the RNA polymerase. The authors also provide the reader with their expert opinion and future perspectives.\r\n\r\nExpert opinion: Interactions made by viral proteins with host factors reveal key functions that are likely usurped by the virus and, as aconsequence, points to known drugs that can be repurposed to fight viral infection and collateral damages that can exacerbate various disease conditions in COVID-19.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":716,"name":"Current understanding on molecular drug targets and emerging treatment strategy for novel coronavirus-19","author":"Khadga Raj, Karamjeet Kaur, G. D. Gupta, Shamsher Singh","doi":"10.1007\/s00210-021-02091-5","abstract":"SARS-CoV-2 is an enveloped positive-sense RNA virus, contain crown-like spikes on its surface, exceptional of large RNA genome, and a special replication machinery. Common symptoms of SARS-CoV-2 include cough, common cold, fever, sore throat, and a variety of severe acute respiratory disease (SARD) such as pneumonia. SARS-CoV-2 infects epithelial cells, T-cells, macrophages, and dendritic cells and also influences the production and implantation of pro-inflammatory cytokines and chemokines. Repurposing of various drugs during this emergency condition can reduce the rate of mortality as well as time and cost. Two druggable protein and enzyme targets have been selected in this review article due to their crucial role in the viral life cycle. The eukaryotic translation initiation factor (eIF4A), cyclophilin, nucleocapsid protein, spike protein, Angiotensin-converting enzyme 2 (ACE2), 3-chymotrypsin-like cysteine protease (3CLpro), and RNA-dependent RNA polymerase (RdRp) play significant role in early and late phase of SARS-CoV-2 replication and translation. This review paper is based on the rationale of inhibiting of various SARS-CoV-2 proteins and enzymes as novel therapeutic approaches for the management and treatment of patients with SARS-CoV-2 infection. We also discussed the structural and functional relationship of different proteins and enzymes to develop therapeutic approaches for novel coronavirus SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":715,"name":"Drug repurposing approach to combating coronavirus: Potential drugs and drug targets","author":"Jimin Xu, Yu Xue, Richard Zhou, Pei-Yong Shi, Hongmin Li, Jia Zhou","doi":"10.1002\/med.21763","abstract":"In the past two decades, three highly pathogenic human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus, and, recently, SARS-CoV-2, have caused pandemics of severe acute respiratory diseases with alarming morbidity and mortality. Due to the lack of specific anti-CoV therapies, the ongoing pandemic of coronavirus disease 2019 (COVID-19) poses a great challenge to clinical management and highlights an urgent need for effective interventions. Drug repurposing is a rapid and feasible strategy to identify effective drugs for combating this deadly infection. In this review, we summarize the therapeutic CoV targets, focus on the existing small molecule drugs that have the potential to be repurposed for existing and emerging CoV infections of the future, and discuss the clinical progress of developing small molecule drugs for COVID-19.","type":"Review","database":"PMC","created":"2021-06-21"},{"id":714,"name":"Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2","author":"Ahmad F. Eweas, Amr A. Alhossary, Ahmed S. Abdel-Moneim4","doi":"10.3389\/fmicb.2020.592908","abstract":"SARS-CoV-2 is a newly emerged coronavirus that causes a respiratory disease with variable severity and fatal consequences. It was first reported in Wuhan and subsequently caused a global pandemic. The viral spike protein binds with the ACE-2 cell surface receptor for entry, while TMPRSS2 triggers its membrane fusion. In addition, RNA dependent RNA polymerase (RdRp), 3\u2032\u20135\u2032 exoribonuclease (nsp14), viral proteases, N, and M proteins are important in different stages of viral replication. Accordingly, they are attractive targets for different antiviral therapeutic agents. Although many antiviral agents have been used in different clinical trials and included in different treatment protocols, the mode of action against SARS-CoV-2 is still not fully understood. Different potential repurposed drugs, including, chloroquine, hydroxychloroquine, ivermectin, remdesivir, and favipiravir, were screened in the present study. Molecular docking of these drugs with different SARS-CoV-2 target proteins, including spike and membrane proteins, RdRp, nucleoproteins, viral proteases, and nsp14, was performed. Moreover, the binding affinities of the human ACE-2 receptor and TMPRSS2 to the different drugs were evaluated. Molecular dynamics simulation and MM-PBSA calculation were also conducted. Ivermectin and remdesivir were found to be the most promising drugs. Our results suggest that both these drugs utilize different mechanisms at the entry and post-entry stages and could be considered potential inhibitors of SARS-CoV-2 replication.","type":"Research","database":"PMC","created":"2021-06-21"},{"id":713,"name":"Exploring existing drugs: proposing potential compounds in the treatment of COVID-19","author":"Eva Rahman Kabir, Nashrah Mustafa, Nahid Nausheen, Mohammad Kawsar Sharif Siam, Easin Uddin Syed","doi":"10.1016\/j.heliyon.2021.e06284","abstract":"The COVID-19 situation had escalated into an unprecedented global crisis in just a few weeks. On the 30th of January 2020, World Health Organization officially declared the COVID-19 epidemic as a public health emergency of international concern. The confirmed cases were reported to exceed 105,856,046 globally, with the death toll of above 2,311,048, according to the dashboard from Johns Hopkins University on the 7th of February, 2021, though the actual figures may be much higher. Conserved regions of the South Asian strains were used to construct a phylogenetic tree to find evolutionary relationships among the novel virus. Off target similarities were searched with other microorganisms that have been previously reported using Basic Local Alignment Search Tool (BLAST). The conserved regions did not match with any previously reported microorganisms or viruses, which confirmed the novelty of SARS-CoV-2. Currently there is no approved drug for the prevention and treatment of COVID-19, but researchers globally are attempting to come up with one or more soon. Therapeutic strategies need to be addressed urgently to combat COVID-19. Successful drug repurposing is a tool that uses old and safe drugs, is time effective and requires lower development costs, and was thus considered for the study. Molecular docking was used for repurposing drugs from our own comprehensive database of approximately 300 highly characterized, existing drugs with known safety profile, to identify compounds that will inhibit the chosen molecular targets - SARS-CoV-2, ACE2, and TMPRSS2. The study has identified and proposed twenty seven candidates for further in vitro and in vivo studies for the treatment of SARS-CoV-2 infection.","type":"Research","database":"PMC","created":"2021-06-21"},{"id":712,"name":"Blockers of the SARS-CoV-2 3a Channel Identified by Targeted Drug Repurposing","author":"Prabhat Pratap Singh Tomar, Miriam Krugliak, Isaiah T. Arkin","doi":"10.3390\/v13030532","abstract":"The etiological agent of the COVID-19 pandemic is SARS-CoV-2. As a member of the Coronaviridae, the enveloped pathogen has several membrane proteins, of which two, E and 3a, were suggested to function as ion channels. In an effort to increase our treatment options, alongside providing new research tools, we have sought to inhibit the 3a channel by targeted drug repurposing. To that end, using three bacteria-based assays, we screened a library of 2839 approved-for-human-use drugs and identified the following potential channel-blockers: Capreomycin, Pentamidine, Spectinomycin, Kasugamycin, Plerixafor, Flumatinib, Litronesib, Darapladib, Floxuridine and Fludarabine. The stage is now set for examining the activity of these compounds in detailed electrophysiological studies and their impact on the whole virus with appropriate biosafety measures.","type":"Research","database":"PubMed","created":"2021-06-14"},{"id":711,"name":"From hydroxychloroquine to ivermectin: what are the anti-viral properties of anti-parasitic drugs to combat SARS-CoV-2?","author":"S Rakedzon, A Neuberger, A J Domb, N Petersiel, E Schwartz","doi":"10.1093\/jtm\/taab005","abstract":"Background\r\nNearly a year into the COVID-19 pandemic, we still lack effective anti-SARS-CoV-2 drugs with substantial impact on mortality rates except for dexamethasone. As the search for effective antiviral agents continues, we aimed to review data on the potential of repurposing antiparasitic drugs against viruses in general, with an emphasis on coronaviruses.\r\n\r\nMethods\r\nWe performed a review by screening in vitro and in vivo studies that assessed the antiviral activity of several antiparasitic agents: chloroquine, hydroxychloroquine (HCQ), mefloquine, artemisinins, ivermectin, nitazoxanide (NTZ), niclosamide, atovaquone and albendazole.\r\n\r\nResults\r\nFor HCQ and chloroquine we found ample in vitro evidence of antiviral activity. Cohort studies that assessed the use of HCQ for COVID-19 reported conflicting results, but randomized controlled trials (RCTs) demonstrated no effect on mortality rates and no substantial clinical benefits of HCQ used either for prevention or treatment of COVID-19. We found two clinical studies of artemisinins and two studies of NTZ for treatment of viruses other than COVID-19, all of which showed mixed results. Ivermectin was evaluated in one RCT and few observational studies, demonstrating conflicting results. As the level of evidence of these data is low, the efficacy of ivermectin against COVID-19 remains to be proven. For chloroquine, HCQ, mefloquine, artemisinins, ivermectin, NTZ and niclosamide, we found in vitro studies showing some effects against a wide array of viruses. We found no relevant studies for atovaquone and albendazole.\r\n\r\nConclusions\r\nAs the search for an effective drug active against SARS-CoV-2 continues, we argue that pre-clinical research of possible antiviral effects of compounds that could have antiviral activity should be conducted. Clinical studies should be conducted when sufficient in vitro evidence exists, and drugs should be introduced into widespread clinical use only after being rigorously tested in RCTs. Such a search may prove beneficial in this pandemic or in outbreaks yet to come.","type":"Review","database":"PubMed","created":"2021-06-14"},{"id":710,"name":"SARS-CoV-2 protein drug targets landscape: a potential pharmacological insight view for the new drug development","author":" Chiranjib Chakraborty, Manojit Bhattacharya, Bidyut Mallick, Ashish Ranjan Sharma, Sang-Soo Lee, Govindasamy Agoramoorthy","doi":"10.1080\/17512433.2021.1874348","abstract":"Introduction: Protein drug targets play a significant choice in different stages of the drug discovery process. There is an urgent need to understand the drug discovery approaches and protein drug targets (PDT) of SARS-CoV-2, with structural insights for the development of SARS-CoV-2 drugs through targeted therapeutic approach.\r\n\r\nAreas covered: We have described the protein as a drug target class and also discussed various drug discovery approaches for SARS-CoV-2 involving the protein drug targets such as drug repurposing study, designing of viral entry inhibitors, viral replication inhibitors, and different enzymes of the virus. We have performed comprehensive literature search from the popular databases such as PubMed Google scholar, Web of Science, and Scopus. Finally, we have illustrated the structural landscape of different significant viral proteins (3 CLpro or Mpro, PLpro, RdRp, helicase, S protein) and host proteins as drug targets (cathepsin L, furin, TMPRSS2, ACE2).\r\n\r\nExpert opinion: The structural landscape of PDT with their binding pockets, and significant residues involved in binding has been discussed further to better understand the PDT and the structure-based drug discovery for SARS-CoV-2. This attempt will increase more therapeutic options, and combination therapies with a multi-target strategy.","type":"Review","database":"PubMed","created":"2021-06-14"},{"id":709,"name":"In Silico Screening of the DrugBank Database to Search for Possible Drugs against SARS-CoV-2","author":"Sebasti\u00e1n A. Cuesta , Jos\u00e9 R. Mora, Edgar A. M\u00e1rquez","doi":"10.3390\/molecules26041100","abstract":"Coronavirus desease 2019 (COVID-19) is responsible for more than 1.80 M deaths worldwide. A Quantitative Structure-Activity Relationships (QSAR) model is developed based on experimental pIC50 values reported for a structurally diverse dataset. A robust model with only five descriptors is found, with values of R2 = 0.897, Q2LOO = 0.854, and Q2ext = 0.876 and complying with all the parameters established in the validation Tropsha\u2019s test. The analysis of the applicability domain (AD) reveals coverage of about 90% for the external test set. Docking and molecular dynamic analysis are performed on the three most relevant biological targets for SARS-CoV-2: main protease, papain-like protease, and RNA-dependent RNA polymerase. A screening of the DrugBank database is executed, predicting the pIC50 value of 6664 drugs, which are IN the AD of the model (coverage = 79%). Fifty-seven possible potent anti-COVID-19 candidates with pIC50 values > 6.6 are identified, and based on a pharmacophore modelling analysis, four compounds of this set can be suggested as potent candidates to be potential inhibitors of SARS-CoV-2. Finally, the biological activity of the compounds was related to the frontier molecular orbitals shapes.","type":"Research","database":"PubMed","created":"2021-06-14"},{"id":708,"name":"Drug repurposing for identification of potential inhibitors against SARS-CoV-2 spike receptor-binding domain: An in silico approach","author":"Santosh Kumar Behera, Namita Mahapatra, Chandra Sekhar Tripathy, Sanghamitra Pati","doi":"10.4103\/ijmr.IJMR_1132_20","abstract":"Background & objectives: The world is currently under the threat of coronavirus disease 2019 (COVID-19) infection, caused by SARS-CoV-2. The objective of the present investigation was to repurpose the drugs with potential antiviral activity against receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein among 56 commercially available drugs. Therefore, an integrative computational approach, using molecular docking, quantum chemical calculation and molecular dynamics, was performed to unzip the effective drug-target interactions between RBD and 56 commercially available drugs. \r\n\r\nMethods: The present in silico approach was based on information of drugs and experimentally derived crystal structure of RBD of SARS-CoV-2 S protein. Molecular docking analysis was performed for RBD against all 56 reported drugs using AutoDock 4.2 tool to screen the drugs with better potential antiviral activity which were further analysed by other computational tools for repurposing potential drug or drugs for COVID-19 therapeutics. \r\n\r\nResults: Drugs such as chalcone, grazoprevir, enzaplatovir, dolutegravir, daclatasvir, tideglusib, presatovir, remdesivir and simeprevir were predicted to be potentially effective antiviral drugs against RBD and could have good COVID-19 therapeutic efficacy. Simeprevir displayed the highest binding affinity and reactivity against RBD with the values of -8.52 kcal\/mol (binding energy) and 9.254 kcal\/mol (band energy gap) among all the 56 drugs under investigation. \r\n\r\nInterpretation & conclusions: In the current investigation, simeprevir was identified as the potential antiviral drug based on the in silico findings in comparison to remdesivir, favipiravir and other 53 drugs. Further, laboratory and clinical investigations are needed to be carried out which will aid in the development of quick therapeutics designed for COVID-19.","type":"Research","database":"PubMed","created":"2021-06-14"},{"id":707,"name":"A molecular docking study of EGCG and theaflavin digallate with the druggable targets of SARS-CoV-2","author":"Susmit Mhatre, Shivraj Naik, Vandana Patravale","doi":"10.1016\/j.compbiomed.2020.104137","abstract":"Background\r\nCOVID-19 is an infectious disease caused by a novel positive-sense single-stranded RNA coronavirus called as SARS-CoV-2. This viral disease is known to infect the respiratory system, eventually leading to pneumonia. Crystallographic studies of the viral structure reveal its mechanism of infection as well as active binding sites and the druggable targets as scope for treatment of COVID-19.\r\n\r\nHypothesis\r\nThe role of tea polyphenols in prophylaxis and treatment of COVID-19 was established in this study.\r\n\r\nStudy design\r\nMolecular docking interactions of tea polyphenols with some of the possible binding sites of SARS-CoV-2 were performed.\r\n\r\nMaterials and methods\r\nFrom various studies on the SARS-CoV-2 reported in the literature, we chose possible drug targets (Chymotrypsin-like protease, RNA dependant RNA polymerase, Papain like protease, Spike RBD and ACE2 receptor with spike RBD) which are vital proteins. These receptors were docked against two tea polyphenols, Epigallocatechin gallate (EGCG) from green tea and Theaflavin digallate (TF3) from black tea. These polyphenols have been previously reviewed for their antiviral activities, especially against single-stranded RNA viruses. Two antiviral drugs, Remdesivir and Favipiravir were studied for comparative docking results.\r\n\r\nResults\r\nA comparative study of docking scores and the type of interactions of EGCG, TF3 with the possible targets of COVID-19 showed that the tea polyphenols had good docking scores with significant in-silico activity.\r\n\r\nConclusion\r\nThese results can provide a lead in exploring both the tea polyphenols in prophylaxis as well as treatment of COVID-19.","type":"Research","database":"PubMed","created":"2021-06-14"},{"id":706,"name":"A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 spike protein to ACE2","author":"Kaleb B. Tsegay, Christiana M. Adeyemi, Edward P. Gniffke, D. Noah Sather, John K. Walker, Stephen E. P. Smith","doi":"10.1101\/2021.04.08.439071","abstract":"Repurposed drugs that block the interaction between the SARS-CoV-2 spike protein\r\nand its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or\r\nprophylactics. Here, we screened 2701 compounds from a commercial library of drugs\r\napproved by international regulatory agencies for their ability to inhibit the binding of\r\nrecombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We\r\nidentified 56 compounds that inhibited binding by <90%, measured the EC50 of binding\r\ninhibition, and computationally modeled the docking of the best inhibitors to both Spike\r\nand ACE2. These results highlight an effective screening approach to identify\r\ncompounds capable of disrupting the Spike-ACE2 interaction as well as identifying\r\nseveral potential inhibitors that could serve as templates for future drug discovery\r\nefforts.\r\n","type":"Research","database":"BioRxiv","created":"2021-06-14"},{"id":705,"name":"Anti-Rheumatic Drugs for the Fight Against the Novel Coronavirus Infection (SARSCoV-2): What is the Evidence?","author":"Eleftherios Pelechas , Vassiliki Drossou , Paraskevi V. Voulgari , Alexandros A. Drosos ","doi":"10.31138\/mjr.31.3.259","abstract":"SARS-CoV-2 is a positive-sense single-stranded RNA virus that causes the COVID-19 infection.\r\nSpike proteins are the most important proteins found on its capsule using the host\u2019s ACE2 receptors\r\nto invade respiratory cells. The natural course of the COVID-19 infection is variable, from asymptomatic to severe and potentially fatal. A small percentage of the severely infected patients will end up in\r\nan intensive care unit for ventilatory support. Elderly male patients with pre-existing medical conditions and smokers are at a disproportionate high risk to develop severe complications. Studies have\r\nshown that deaths occur due to a dysregulated immune system that overreacts, producing a plethora of cytokines, leading to the so-called \u201ccytokine storm\u201d phenomenon. In this direction, many drugs\r\nthat are used in the everyday practice of Rheumatologists have been used. Indeed, pro-inflammatory\r\ncytokines such as the IL-1 and IL-6 have been shown to be the pivotal cytokines expressed, and\r\nanti-cytokine treatment has been tried so far with various results. In addition, hydroxychloroquine,\r\nan antimalarial drug, has been shown to reduce COVID-19 symptoms. Other drugs have also been\r\nused, such as intravenous pulses of immunoglobulins, and colchicine. Robust clinical trials are needed in order to find the suitable treatment. Current data indicate that hydroxychloroquine and cytokine\r\ntargeting therapies may prove helpful in the fight of SARS-CoV-2 in appropriately selected patients. ","type":"Review","database":"PMC","created":"2021-06-14"},{"id":704,"name":"A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework","author":"Raul P\u00e9rez-Moraga, Jaume For\u00e9s-Martos, Beatriz Suay-Garc\u00eda, Jean-Louis Duval, Antonio Falc\u00f3, Joan Climent","doi":"10.3390\/pharmaceutics13040488","abstract":"Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 116 million cases and 2.5 million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We applied a novel computational pipeline aimed to accelerate the process of identifying drug repurposing candidates which allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 endoribonuclease, and NSP12 RNA-dependent RNA polymerase), which included rutin, dexamethasone, and vemurafenib. This is the first time that a topological data analysis (TDA)-based strategy has been used to compare a massive number of protein structures with the final objective of performing drug repurposing to treat SARS-CoV-2 infection.","type":"Research","database":"PMC","created":"2021-05-31"},{"id":703,"name":"Repositioned Drugs for COVID-19\u2014the Impact on Multiple Organs","author":"Christina Chan, Sean T. Foster, Kayla G. Chan, Matthew J. Cacace, Shay L. Ladd, Caleb T. Sandum, Paul T. Wright, Brett Volmert, Weiyang Yang, Aitor Aguirre, Wen Li, Neil T. Wright ","doi":"10.1007\/s42399-021-00874-8","abstract":"This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs.","type":"Review","database":"PMC","created":"2021-05-31"},{"id":702,"name":"Inhibitory efficiency of potential drugs against SARS-CoV-2 by blocking human angiotensin converting enzyme-2: Virtual screening and molecular dynamics study","author":"Abdul Ashik Khana, Nabajyoti Baildya, Tanmoy Dutta, Narendra Nath Ghosh","doi":"10.1016\/j.micpath.2021.104762","abstract":"Till date millions of people are infected by SARS-CoV-2 throughout the world, while no potential therapeutics or vaccines are available to combat this deadly virus. Blocking of human angiotensin-converting enzyme 2 (ACE-2) receptor, the binding site of SARS-CoV-2 spike protein, an effective strategy to discover a drug for COVID-19. Herein we have selected 24 anti-bacterial and anti-viral drugs and made a comprehensive analysis by screened them virtually against ACE-2 receptor to find the best blocker by molecular docking and molecular dynamics studies. Analysis of results revealed that, Cefpiramide (CPM) showed the highest binding affinity of \u22129.1 kcal\/mol. Furthermore, MD study for 10 ns and evaluation of parameters like RMSD, RMSF, radius of gyration, solvent accessible surface area analysis confirmed that CPM effectively binds and blocks ACE-2 receptor efficiently.","type":"Research","database":"PubMed","created":"2021-05-31"},{"id":701,"name":"Drug repositioning to target NSP15 protein on SARS-CoV-2 as possible COVID-19 treatment","author":" Yudibeth Sixto-L\u00f3pez Ph. D., Marlet Mart\u00ednez-Archundia","doi":"10.1002\/jcc.26512","abstract":"SARS-CoV and SARS-CoV-2 belong to the subfamily Coronaviridae and infect humans, they are constituted by four structural proteins: Spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N), and nonstructural proteins, such as Nsp15 protein which is exclusively present on nidoviruses and is absent in other RNA viruses, making it an ideal target in the field of drug design. A virtual screening strategy to search for potential drugs was proposed, using molecular docking to explore a library of approved drugs available in the DrugBank database in order to identify possible NSP15 inhibitors to treat Covid19 disease. We found from the docking analysis that the antiviral drugs: Paritaprevir and Elbasvir, currently both approved for hepatitis C treatment which showed some of the lowest free binding energy values were considered as repositioning drugs to combat SARS-CoV-2. Furthermore, molecular dynamics simulations of the Apo and Holo-Nsp15 systems were performed in order to get insights about the stability of these protein-ligand complexes.","type":"Research","database":"PubMed","created":"2021-05-31"},{"id":700,"name":"In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19 ","author":" Carolina Q Sacramento, Natalia Fintelman-Rodrigues, Jairo R Temerozo, Aline de Paula Dias Da Silva, Suelen da Silva Gomes Dias, Carine dos Santos da Silva, Andr\u00e9 C Ferreira, Mayara Mattos, Camila R R P\u00e3o, Caroline S de Freitas, Vinicius Cardoso Soares, Lucas Villas B\u00f4as Hoelz, T\u00e1cio Vin\u00edcio Amorim Fernandes, Frederico Silva Castelo Branco, M\u00f4nica Macedo Bastos, N\u00fabia Boechat, Felipe B Saraiva, Marcelo Alves Ferreira, Steffen Jockusch, Xuanting Wang, Chuanjuan Tao, Minchen Chien, Wei Xie, Dinsha","doi":"10.1093\/jac\/dkab072","abstract":"Background\r\nCurrent approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity.\r\n\r\nMethods\r\nSARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir\u2019s dose and schedule to maximize the probability of success for COVID-19.\r\n\r\nResults\r\nDaclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1\u2009\u03bcM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans.\r\n\r\nConclusions\r\nDaclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.","type":"Research","database":"PMC","created":"2021-05-19"},{"id":699,"name":"Astemizole as a drug to inhibit the effect of SARS-COV-2 in vitro","author":"Xiangjun Wang, Jiayu Lu, Shuai Ge, Yajing Hou, Tian Hu, Yuexin Lv, Cheng Wang, Huaizhen He","doi":"10.1016\/j.micpath.2021.104929","abstract":"Since the beginning of December 2019, a novel Coronavirus severe respiratory disease, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which also been termed 2019-new CoV (2019-nCoV), has continued to spread worldwide. As of August 27, 2020, a total of 24,232,429 people have been infected and 826,518 people have died. In our study, we found that astemizole can antagonize ACE2 and inhibit the entry of SARS-COV-2 spike pseudovirus into ACE2-expressed HEK293T cells (ACE2hi cells). We analysied the binding character of astemizole to ACE2 by molecular docking and surface plasmon resonance (SPR) assays and molecule docking, SARS-COV-2 spike pseudotype virus was also taken to investigate the suppression viropexis effect of astemizole. The results showed that astemizole can bind to the ACE2 receptor and inhibit the invasion of SARS-COV-2 Spike pseudoviruses. Thus astemizole represent potential drug candidates that can be re-used in anti-coronavirus therapies.","type":"Research","database":"PubMed","created":"2021-05-19"},{"id":698,"name":"Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents","author":" Austin N. Spratt, Fabio Gallazzi, Thomas P. Quinn, Christian L. Lorson, Anders S\u00f6nnerborg, Kamal Singh","doi":"10.1080\/13543776.2021.1884224","abstract":"Introduction: Coronaviruses encode a helicase that is essential for viral replication and represents an excellent antiviral target. However, only a few coronavirus helicase inhibitors have been patented. These patents include drug-like compound SSYA10-001, aryl diketo acids (ADK), and dihydroxychromones. Additionally, adamantane-derived bananins, natural flavonoids, one acrylamide derivative [(E)-3-(furan-2-yl)-N-(4-sulfamoylphenyl)acrylamide], a purine derivative (7-ethyl-8-mercapto-3-methyl-3,7-dihydro-1 H-purine-2,6-dione), and a few bismuth complexes. The IC50 of patented inhibitors ranges between 0.82 \u03bcM and 8.95 \u03bcM, depending upon the assays used. Considering the urgency of clinical interventions against Coronavirus Disease-19 (COVID-19), it is important to consider developing antiviral portfolios consisting of small molecules.\r\n\r\nAreas covered: This review examines coronavirus helicases as antiviral targets, and the potential of previously patented and experimental compounds to inhibit the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) helicase.\r\n\r\nExpert opinion: Small molecule coronavirus helicase inhibitors represent attractive pharmacological modalities for the treatment of coronaviruses such as SARS-CoV and SARS-CoV-2. Rightfully so, the current emphasis is focused upon the development of vaccines. However, vaccines may not work for everyone and broad-based adoption of vaccinations is an increasingly challenging societal endeavor. Therefore, it is important to develop additional pharmacological antivirals against the highly conserved coronavirus helicases to broadly protect against this and subsequent coronavirus epidemics.","type":"Review","database":"PubMed","created":"2021-05-19"},{"id":697,"name":"A review on drug repurposing applicable to COVID-19","author":"Serena Dotolo, Anna Marabotti, Angelo Facchiano, Roberto Tagliaferri","doi":"10.1093\/bib\/bbaa288","abstract":"Drug repurposing involves the identification of new applications for existing drugs at a lower cost and in a shorter time. There are different computational drug-repurposing strategies and some of these approaches have been applied to the coronavirus disease 2019 (COVID-19) pandemic. Computational drug-repositioning approaches applied to COVID-19 can be broadly categorized into (i) network-based models, (ii) structure-based approaches and (iii) artificial intelligence (AI) approaches. Network-based approaches are divided into two categories: network-based clustering approaches and network-based propagation approaches. Both of them allowed to annotate some important patterns, to identify proteins that are functionally associated with COVID-19 and to discover novel drug\u2013disease or drug\u2013target relationships useful for new therapies. Structure-based approaches allowed to identify small chemical compounds able to bind macromolecular targets to evaluate how a chemical compound can interact with the biological counterpart, trying to find new applications for existing drugs. AI-based networks appear, at the moment, less relevant since they need more data for their application.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":696,"name":"Kakkonto, shosaikoto, Platycodon grandiflorum root, and gypsum (a Japanese original combination drug known as saikatsugekito): Pharmacological review of its activity against viral infections and respiratory inflammatory conditions and a discussion of its applications to COVID\u201019","author":"Ryutaro Arita, Rie Ono, Natsumi Saito, Shin Takayama, Takao Namiki, Takashi Ito, Tadashi Ishii","doi":"10.1002\/tkm2.1258","abstract":"Aim\r\nTraditional Japanese (Kampo) medicine has been used to treat viral infectious diseases. In particular, saikatsugekito (a combination drug of kakkonto, shosaikoto, Platicodon glandiflorum root, and gypsum) has been reported to be useful during the past influenza pandemic. The severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) has spread worldwide, causing the novel coronavirus disease (COVID\u201019) to emerge as a pandemic. In this article, we conducted a literature review on the pharmacological activities of the components present in saikatsugekito against viral infection and respiratory inflammation.\r\n\r\nMethods\r\nWe searched PubMed and the Cochrane Library for English articles, as well as Ichushi and J\u2010stage for Japanese articles. Articles published until January 1, 2000 were retrieved using the keywords \u2018kakkonto\u2019, \u2018shosaikoto\u2019, \u2018Platycodon\u2019, and \u2018gypsum\u2019. We then extracted articles on basic research investigating viral infections, inflammation, cytokine, the immune response, and lung tissue damage.\r\n\r\nResults\r\nWe extracted 28 eligible articles. Kampo medicines have antiviral activities by interfering with the attachment, internalization, replication, progeny virion release, and cell\u2010to\u2010cell spreading of single\u2010strand RNA viruses. They also enhance the immunomodulating activities of the host, including cytokine production, regulation of multiple immune cells, and protection from lung tissue injury. Furthermore, Kampo medicine has been found to regulate body temperature and airway mucin release.\r\n\r\nConclusion\r\nThe results demonstrated that Kampo medicine has therapeutic activities against single\u2010strand RNA virus infections and respiratory inflammation, and may also have activities against SARS\u2010CoV\u20102. Further research is required to investigate the activity of Kampo medicines, such as saikatsugekito, against SARS\u2010CoV\u20102.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":695,"name":"Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review","author":"Kawthar Mohamed, Niloufar Yazdanpanah, Amene Saghazadeh, Nima Rezaei","doi":"10.1016\/j.bioorg.2020.104490","abstract":"Background\r\nSince the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19.\r\n\r\nMethods\r\nWe undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19.\r\n\r\nResults\r\nTwenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS\/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole).\r\n\r\nConclusions\r\nThe present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":694,"name":"Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review","author":"Bruno Silva Andrade, Fernanda de Souza Rangel, Naiane Oliveira Santos, Andria dos Santos Freitas, Wagner Rodrigues de Assis Soares, S\u00e9rgio Siqueira, Debmalya Barh, Arist\u00f3teles G\u00f3es-Neto, Alexander Birbrair, Vasco Ariston de Carvalho Azevedo","doi":"10.3389\/fphar.2020.590598","abstract":"The SARS-CoV-2 outbreak originally appeared in China in December 2019 and became a global pandemic in March 2020. This infectious disease has directly affected public health and the world economy. Several palliative therapeutic treatments and prophylaxis strategies have been used to control the progress of this viral infection, including pre-(PrEP) and post-exposure prophylaxis. On the other hand, research groups around the world are still studying novel drug prophylaxis and treatment using repurposing approaches, as well as vaccination options, which are in different pre-clinical and clinical testing phases. This systematic review evaluated 1,228 articles from the PubMed and Scopus indexing databases, following the Kitchenham bibliographic searching protocol, with the aim to list drug candidates, potentially approved to be used as new options for SARS-CoV-2 prophylaxis clinical trials and medical protocols. In searching protocol, we used the following keywords: \u201cCovid-19 or SARS-CoV-2\u201d or \u201cCoronavirus or 2019 nCoV,\u201d \u201cprophylaxis,\u201d \u201cprophylactic,\u201d \u201cpre-exposure,\u201d \u201cCOVID-19 or SARS-CoV-2 Chemoprophylaxis,\u201d \u201crepurposed,\u201d \u201cstrategies,\u201d \u201cclinical,\u201d \u201ctrials,\u201d \u201canti-SARS-CoV-2,\u201d \u201canti-covid-19,\u201d \u201cAntiviral,\u201d \u201cTherapy prevention in vitro,\u201d in cells \u201cand\u201d human testing. After all protocol steps, we selected 60 articles that included: 15 studies with clinical data, 22 studies that used in vitro experiments, seven studies using animal models, and 18 studies performed with in silico experiments. Additionally, we included more 22 compounds between FDA approved drugs and drug-like like molecules, which were tested in large-scale screenings, as well as those repurposed approved drugs with new mechanism of actions. The drugs selected in this review can assist clinical studies and medical guidelines on the rational repurposing of known antiviral drugs for COVID-19 prophylaxis.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":693,"name":"Systematic Review on the Therapeutic Options for COVID-19: Clinical Evidence of Drug Efficacy and Implications","author":"Abubakar AR, Sani IH, Godman B, Kumar S, Islam S, Jahan I, Haque M","doi":"10.2147\/IDR.S289037","abstract":"Abstract: A novel coronavirus-2 (SARS-CoV-2) was first identified in Wuhan, China, and quickly spread globally. Several treatments have been proposed, many of which have proven ineffective. Consequently, there is a need to review the published evidence of drug clinical trials to guide future prescribing. A systematic review of published clinical trials and retrospective observational studies was carried out. The search was made using PubMed, Embase, MEDLINE, and China National Knowledge Infrastructure (CNKI) databases. Articles published between January 2020 and October 2020 and written in the English language were retrieved and included in the study. Researches that used traditional medicine, in-vitro and in-vivo animal studies, as well as reviews were excluded. Seventy-three relevant articles that fulfilled the inclusion criteria were finally selected and reviewed. Hydroxychloroquine, chloroquine, and azithromycin produced no clinical evidence of efficacy in randomized controlled clinical trials (RCT). However, retrospective observational studies reported the efficacy of remdesivir and lopinavir\/ritonavir in reducing viral load, although there have been concerns with lopinavir\/ritonavir and, more recently, remdesivir. Recently, tocilizumab, dexamethasone, and methylprednisolone significantly relieved lung inflammation and decreased mortality in patients with severe COVID-19. In addition, convalescent plasma was effective in boosting strong immunity among patients with mild COVID-19. There is currently no single worldwide approved therapeutic option for patients with COVID-19 despite the initial hype with medicines, including hydroxychloroquine. Nonetheless, dexamethasone has shown promise in symptomatic treatment and convalescent plasma in boosting immunity. New treatments are currently being researched, and the findings will be reported accordingly to provide evidence-based guidance for prescribers and policymakers.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":692,"name":"Repurposing of Biologic and Targeted Synthetic Anti-Rheumatic Drugs in COVID-19 and Hyper-Inflammation: A Comprehensive Review of Available and Emerging Evidence at the Peak of the Pandemic","author":"Giulio Cavalli, Nicola Farina, Corrado Campochiaro, Giacomo De Luca, Emanuel Della-Torre, Alessandro Tomelleri, Lorenzo Dagna","doi":"10.3389\/fphar.2020.598308","abstract":"Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":691,"name":"Anti-COVID-19 drug candidates: A review on potential biological activities of natural products in the management of new coronavirus infection","author":"Anchalee Prasansuklab, Atsadang Theerasri, Panthakarn Rangsinth, Chanin Sillapachaiyaporn, Siriporn Chuchawankul,Tewin Tencomnao","doi":"10.1016\/j.jtcme.2020.12.001","abstract":"Background and aim\r\nThe novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now become a worldwide pandemic bringing over 71 million confirmed cases, while the specific drugs and vaccines approved for this disease are still limited regarding their effectiveness and adverse events. Since virus incidences are still on rise, infectivity and mortality may also rise in the near future, natural products are highly considered to be valuable sources for the discovery of new antiviral drugs against SARS-CoV-2. This present review aims to comprehensively summarize the up-to-date scientific literatures on biological activities of plant- and mushroom-derived compounds relevant to mechanistic targets involved in SARS-CoV-2 infection and inflammatory-associated pathogenesis, including viral entry, replication and release, and the renin-angiotensin-aldosterone system (RAAS).\r\n\r\nExperimental procedure\r\nData were retrieved from a literature search available on PubMed, Scopus and Google Scholar databases and collected until the end of May 2020. The findings from in vitro cell and non-cell based studies were considered, while the results of in silico studies were excluded.\r\n\r\nResults and conclusion\r\nBased on the previous findings in SARS-CoV studies, except in silico molecular docking analysis, herein, we provide a total of 150 natural compounds as potential candidates for development of new anti-COVID-19 drugs with higher efficacy and lower toxicity than the existing therapeutic agents. Several natural compounds have showed their promising actions on multiple therapeutic targets, which should be further explored. Among them, quercetin, one of the most abundant of plant flavonoids, is proposed as a lead candidate with its ability on the virus side to inhibit SARS-CoV spike protein-angiotensin-converting enzyme 2 (ACE2) interaction, viral protease and helicase activities, as well as on the host cell side to inhibit ACE activity and increase intracellular zinc level.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":690,"name":"Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-\u03baB: A Systematic Review","author":"Apparao Peddapalli, Manish Gehani, Arunasree M. Kalle, Siva R. Peddapalli, Angela E. Peter, Shashwat Sharad","doi":"10.3390\/v13030378","abstract":"The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27 October 2020, irrespective of type of article, country, or region. Joanna Briggs Institute\u2019s design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-\u03baB (NF-\u03baB) signaling as a common pathway of excess immune response. Molecules blocking NF-\u03baB or targeting downstream effectors like Tumour Necrosis Factor \u03b1 (TNF\u03b1) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-\u03baB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1\u03b2, TNF-\u03b1, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":689,"name":"Developing new drugs that activate the protective arm of the renin\u2013angiotensin system as a potential treatment for respiratory failure in COVID-19 patients","author":"Mathilde Latil, Serge Camelo, Stanislas Veillet, Ren\u00e9 Lafont,Pierre J.Dilda","doi":"10.1016\/j.drudis.2021.02.010","abstract":"COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has reached pandemic proportions with negative impacts on global health, the world economy and human society. The clinical picture of COVID-19, and the fact that Angiotensin converting enzyme 2 (ACE2) is a receptor of SARS-CoV-2, suggests that SARS-CoV-2 infection induces an imbalance in the renin\u2013angiotensin system (RAS). We review clinical strategies that are attempting to rebalance the RAS in COVID-19 patients by using ACE inhibitors, angiotensin receptor blockers, or agonists of angiotensin-II receptor type 2 or Mas receptor (MasR). We also propose that the new MasR activator BIO101, a pharmaceutical grade formulation of 20-hydroxyecdysone that has anti-inflammatory, anti-fibrotic and cardioprotective properties, could restore RAS balance and improve the health of COVID-19 patients who have severe pneumonia.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":688,"name":"Artificial Intelligence for COVID-19 Drug Discovery and Vaccine Development","author":"Arash Keshavarzi Arshadi, Julia Webb, Milad Salem, Emmanuel Cruz, Stacie Calad-Thomson, Niloofar Ghadirian, Jennifer Collins, Elena Diez-Cecilia, Brendan Kelly, Hani Goodarzi,  Jiann Shiun Yuan","doi":"10.3389\/frai.2020.00065","abstract":"SARS-COV-2 has roused the scientific community with a call to action to combat the growing pandemic. At the time of this writing, there are as yet no novel antiviral agents or approved vaccines available for deployment as a frontline defense. Understanding the pathobiology of COVID-19 could aid scientists in their discovery of potent antivirals by elucidating unexplored viral pathways. One method for accomplishing this is the leveraging of computational methods to discover new candidate drugs and vaccines in silico. In the last decade, machine learning-based models, trained on specific biomolecules, have offered inexpensive and rapid implementation methods for the discovery of effective viral therapies. Given a target biomolecule, these models are capable of predicting inhibitor candidates in a structural-based manner. If enough data are presented to a model, it can aid the search for a drug or vaccine candidate by identifying patterns within the data. In this review, we focus on the recent advances of COVID-19 drug and vaccine development using artificial intelligence and the potential of intelligent training for the discovery of COVID-19 therapeutics. To facilitate applications of deep learning for SARS-COV-2, we highlight multiple molecular targets of COVID-19, inhibition of which may increase patient survival. Moreover, we present CoronaDB-AI, a dataset of compounds, peptides, and epitopes discovered either in silico or in vitro that can be potentially used for training models in order to extract COVID-19 treatment. The information and datasets provided in this review can be used to train deep learning-based models and accelerate the discovery of effective viral therapies.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":687,"name":"Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update","author":"Gaurav Joshiab, Shikha Thakur, Mayank, Ramarao Poduri","doi":"10.1016\/j.fct.2021.112106","abstract":"The review summarizes chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) and its utility in Covid-19. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic. This led to an upsurge in the scientific arena with multiple research and review articles along with expert opinions and commentaries. The HCQ has received mixed judgements so far about its efficacy to be used in Covid-19 patients in a limited trial conducted all across the Globe. The purpose of our article is to put forth the history, pharmacodynamics, and pharmacokinetics, along with the existing studies favouring and disapproving the role of HCQ in the treatment of Covid-19. We grouped HCQ use at three stages, this includes HCQ for i. prophylactic use by asymptomatic health workers or peoples at higher risk; ii. patients having mild symptoms; iii. patients with extreme symptoms. The review critically discusses the underlying plausible reasons and mechanisms exploring HCQ in prophylactic management or treatment of SARS-CoV-2. Furthermore, we have critically analysed the reported pharmacokinetic parameters and compiled the proponent, opponent, or neutral opinions on the use of HCQ in Covid-19. Authors discretion is to conduct more studies considering the optimal dosing regimen and pharmacokinetics assessment.","type":"Review","database":"PMC","created":"2021-05-10"},{"id":686,"name":"The mechanistic rationale of drugs, primary endpoints, geographical distribution of clinical trials against severe acute respiratory syndrome\u2010related coronavirus\u20102: A systematic review","author":"Bhanu Prasad Venkatesulu MD , Viveksandeep Thoguluva Chandrasekar MD , Prashanth Giridhar MD , Pragathee V MBBS , Harsh K. Patel MD , Jacob Manteuffel MD","doi":"10.1002\/jmv.26338","abstract":"There are numerous ongoing studies assessing treatment options for preventing, treating, and managing complications of coronavirus disease\u20102019 disease. The objective of this study was to do a systematic review and critical appraisal of the ongoing clinical trials with an aim to provide insight into the various interventions tested, clinical rationale, geographical distribution of the trials as well as the endpoints assessed in the studies. ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and PubMed were assessed till 11 May 2020. The search resulted in 3242 ongoing studies of which 829 studies were included. There are 134 different drug\u2010based interventions being assessed in 463 clinical trials as treatment options China accounts for 35% of all ongoing clinical studies followed by USA 23% and other countries together account for 42%. Amongst the 463 studies assessing drug\u2010based treatment options, studies that are funded by federal and academic institutions are 79.6%, pharmaceutical company\u2010funded studies are 15.11%, and no funding information is available in 5.10%. The definitive outcomes like mortality are being assessed as primary outcome in 22.8% of the studies only and need for ventilator in 6.2% of the studies. Amongst the pharmaceutical company\u2010funded drug\u2010based studies, only 20% of the studies had mortality as the primary outcome. Only 5.5% of the ongoing clinical trials are specifically designed to assess the most vulnerable population like elderly, patients with comorbidities and cancer. Multiple intervention\u2010based clinical studies against severe acute respiratory syndrome\u2010related coronavirus\u20102 are being performed throughout the world with a high concentration of clinical trials in the developed world with concern that of elderly and patients with comorbidities are being underrepresented and definite endpoints like mortality are being assessed in only one\u2010fifth of the studies.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":685,"name":"Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials","author":"Rami A. Al-Horani, Srabani Kar, Kholoud F. Aliter ","doi":"10.3390\/ijms21155224","abstract":"The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and\/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and\/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":684,"name":"Treatments in the COVID-19 pandemic: an update on clinical trials","author":" Yanyi Tao, Liang V. Tang, Yu Hu","doi":"10.1080\/14728214.2020.1773431","abstract":"The coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly and widely around the world, with more than 4,900,000 confirmed cases and more than 320,000 deaths reported as of 20 May 2020. The most common clinical symptoms are fever, cough, fatigue, and dyspnea, and a few patients have some other symptoms such as headache, hemoptysis, and diarrhea [1\u20134]. Previous experience in the treatment of coronavirus, such as SARS-COV and MERS-COV, has provided clinicians with a reference point for dealing with the novel coronavirus. Although there is still no specific drug, the increasing number of COVID-19 related reports around the world provide relevant insights for clinical treatment. This paper will summarize and discuss the current therapeutic drugs treating COVID-19 based on these reports of clinical trials.","type":"Other","database":"PMC","created":"2021-05-09"},{"id":683,"name":"Review of Trials Currently Testing Stem Cells for Treatment of Respiratory Diseases: Facts Known to Date and Possible Applications to COVID-19","author":"Fernanda Majolo, Guilherme Liberato da Silva, Lucas Vieira, Lu\u00eds Fernando Saraiva Macedo Timmers, Stefan Laufer, M\u00e1rcia In\u00eas Goettert","doi":"10.1007\/s12015-020-10033-6","abstract":"Therapeutic clinical and preclinical studies using cultured cells are on the rise, especially now that the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a \u201cpublic health emergency of international concern\u201d, in January, 2020. Thus, this study aims to review the outcomes of ongoing clinical studies on stem cells in Severe Acute Respiratory Syndrome (SARS), Acute Respiratory Distress Syndrome (ARDS), and Middle East Respiratory Syndrome (MERS). The results will be associated with possible applications to COVID-19. Only three clinical trials related to stem cells are considered complete, whereby two are in Phase 1 and one is in Phase 2. Basically, the ongoing studies on coronavirus are using mesenchymal stem cells (MSCs) derived from bone marrow or the umbilical cord to demonstrate their feasibility, safety, and tolerability. The studies not related to coronavirus are all in ARDS conditions; four of them are in Phase 1 and three in Phase 2. With the COVID-19 boom, many clinical trials are being carried out using different sources with an emphasis on MSC-based therapy used to inhibit inflammation. One of the biggest challenges in the current treatment of COVID-19 is the cytokine storm, however MSCs can prevent or mitigate this cytokine storm through their immunomodulatory capacity. We look forward to the results of the ongoing clinical trials to find a treatment for the disease. Researchers around the world are joining forces to help fight COVID-19. Stem cells used in the current clinical studies are a new therapeutic promise for COVID-19 where pharmacological treatments seem insufficient.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":682,"name":"No benefit of hydroxychloroquine in COVID-19: Results of Systematic Review and Meta-Analysis of Randomized Controlled Trials","author":"Dr Subodh Kumar Pathak, Dr Abhijeet Ashok Salunke, Dr Praveen Thivari, Apurva Pandey, Dr Kunal Nandy, Dr Harish V K Ratna, Dr Sanjay Pandey, Dr Jasneet Chawla, Dr Jalil Mujawar, Dr Anant Dhanwate, Dr Vivek Menon","doi":"10.1016\/j.dsx.2020.08.033","abstract":"Background and aims\r\nCoronavirus pandemic is currently a global public health emergency with no definitive treatment guidelines. We conducted a systematic review and meta-analysis of the literature evaluating the efficacy of hydroxychloroquine and its related formulations in COVID-19 patients.\r\n\r\nMethods\r\nA systematic search of PubMed, Scopus, MedRxiv data and Cochrane Central Register of Clinical Trials for published articles that reported the outcomes of COVID-19 patients treated with hydroxychloroquine or its compounds was done. We identified 1071 published studies and 7 studies were included in the analysis.\r\n\r\nResults\r\nThe study population consisted of a total of 4984 patients, of which 1721 (34.5%) received hydroxychloroquine or its congeners (HCQ group) while 3091 (62.01%) received standard of care or had included antiviral medication (control group). The pooled estimate of successful treatment in the hydroxychloroquine group and the control group was 77.45% and 77.87% respectively, which indicated similar clinical outcomes in patients treated with hydroxychloroquine compared to the control group. The odds ratio of a favourable outcome with hydroxychloroquine was 1.11 (95 CI 0.72 to 1.69) (p = 0.20). The pooled risk difference of favourable outcome with hydroxychloroquine versus control group was 0.00 (95 CI -0.03 to 0.03) which was statistically not significant (p = 0.10).\r\n\r\nConclusions: The present evidence shows no benefit of hydroxychloroquine in patients affected by mild to moderate COVID-19 disease. However, now several trials on HCQ are ongoing and hopefully more data will be available soon. Hence, the management of COVID-19 is set to change for better in the future.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":681,"name":"Clinical Trials of Repurposed Antivirals for SARS-CoV-2","author":"Miguel Angel Martinez","doi":"10.1128\/AAC.01101-20","abstract":"The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferons, and hydroxychloroquine. Unfortunately, the first open-label, randomized, controlled trials are showing poor efficacy of these repurposed drugs. These results highlight the necessity of identifying and characterizing specific and potent SARS-CoV-2 antivirals.","type":"Comment","database":"PMC","created":"2021-05-09"},{"id":680,"name":"Overview of the First 6 Months of Clinical Trials for COVID-19 Pharmacotherapy: The Most Studied Drugs","author":"Maria Laura Idda, Dorian Soru, Matteo Floris","doi":"10.3389\/fpubh.2020.00497","abstract":"SARS-CoV-2 rapidly spread from China until it was defined a pandemic by WHO in March 2020. Related scientific papers have rapidly extended information regarding the diagnosis, treatment and epidemiology of COVID-19 infection. To date, no vaccine or definitive treatment is available to defeat the virus and therapies are mainly based on existing drugs used to treat other conditions. Existing therapies used in several clinical trials work by affecting the biology of COVID-19 and\/or counteracting the harmful host excessive immune response. Here, we have reviewed 526 ongoing clinical trials for COVID-19 to provide a perspective on the first 6 months of global efforts to identify an effective therapy. The drugs most actively tested in various centers include hydroxychloroquine, ritonavir, azithromycin, tocilizumab, lopinavir chloroquine and ivermectin. Our analysis shows that most clinical trials focus on a small number of candidate drugs (namely hydroxychloroquine and chloroquine representing 25% of total clinical trials) while underestimating the potential of other promising drugs. A global coordination in clinical trial management could avoid duplications and increase the effectiveness of the response to the global challenge.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":679,"name":"Zinc and COVID-19: Basis of Current Clinical Trials","author":"Amit Pal, Rosanna Squitti, Mario Picozza, Anil Pawar, Mauro Rongioletti, Atanu Kumar Dutta, Sibasish Sahoo, Kalyan Goswami, Praveen Sharma, Rajendra Prasad ","doi":"10.1007\/s12011-020-02437-9","abstract":"Coronavirus disease-2019 (COVID-19) pandemic continues to threaten patients, societies, and economic and healthcare systems around the world. Like many other diseases, the host immune system determines the progress of COVID-19 and fatality. Modulation of inflammatory response and cytokine production using immunonutrition is a novel concept that has been applied to other diseases as well. Zinc, one of the anti-inflammatory and antioxidant micronutrient found in food with well-established role in immunity, is currently being used in some clinical trials against COVID-19. This review integrates the contemporary studies of role of zinc in antiviral immunity along with discussing its potential role against COVID-19, and ongoing COVID-19 clinical trials using zinc.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":678,"name":"Combating the Pandemic COVID-19: Clinical Trials, Therapies and Perspectives","author":"Kotta Sabna, Aldawsari Hibah Mubarak, Badr-Eldin Shaimaa M., Alhakamy Nabil Abdulhafiz, Md Shadab, Nair Anroop B., Deb Pran Kishore","doi":"10.3389\/fmolb.2020.606393","abstract":"The coronavirus disease-19 (COVID-19) is caused due to the infection by a unique single stranded enveloped RNA virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The COVID-19 has claimed many lives around the globe, and a promising solution to end this pandemic is still awaited. Till date neither an exact antiviral drug nor a vaccine is available in the market for public use to cure or control this pandemic. Repurposed drugs and supportive measures are the only available treatment options. This systematic review focuses on different treatment strategies based on various clinical studies. The review discusses all the current treatment plans and probable future strategies obtained as a result of a systematic search in PubMed and Science Direct database. All the possible options for the treatment as well as prophylaxis of COVID-19 are discussed. Apart from this, the article provides details on the clinical trials related to COVID-19, which are registered under ClinicalTrials.gov. Potential of drugs based on the previous researches on SARS-CoV, MERS-CoV, Ebola, influenza, etc. which fall under the same category of coronavirus are also emphasized. Information on cell-based and immunology-based approaches is also provided. In addition, miscellaneous therapeutic approaches and adjunctive therapies are discussed. The drug repurposing options, as evidenced from various in vitro and in silico models, are also covered including the possible future solutions to this pandemic.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":677,"name":"Clinical trial protocols of repurposed prophylaxis for COVID-19: A review","author":"E. Sallard, D. Belhadi, F.-X. Lescure, Y. Yazdanpanah, N. Peiffer-Smadja","doi":"10.1016\/j.medmal.2020.09.013","abstract":"Efficient therapeutic strategies are needed to counter the COVID-19 pandemic, caused by the SARS-CoV-2 virus. In a context where specific vaccines are not yet available, the containment of the pandemic would be facilitated with efficient prophylaxis. We screened several clinical trials repositories and platforms in search of the prophylactic strategies being investigated against COVID-19 in July 2020. Up to July 5, 2020, only one clinical trial result was published, although we found 112 clinical trial protocols targeting medical workers (n = 70, 63%), patients relatives (n = 20, 18%) or individuals at risk of severe COVID-19 (n = 14, 13%). (Hydroxy)chloroquine was the most frequently evaluated treatment (n = 69, 62%), before BCG vaccine (n = 12, 11%), this followed by numerous antivirals and immune enhancers. Ninety-eight (88%) clinical trials were randomized with a median of planned inclusions of 530 (IQR 258\u20131299). Both pre- and post-exposure prophylaxes are investigated.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":676,"name":"Reviews on Biological Activity, Clinical Trial and Synthesis Progress of Small Molecules for the Treatment of COVID-19","author":"Dingzhong Li, Jianbing Hu, Dian Li, Weijun Yang, Shuang-Feng Yin, Renhua Qiu ","doi":"10.1007\/s41061-020-00318-2","abstract":"COVID-19 has broken out rapidly in nearly all countries worldwide, and has blossomed into a pandemic. Since the beginning of the spread of COVID-19, many scientists have been cooperating to study a vast array of old drugs and new clinical trial drugs to discover potent drugs with anti-COVID-19 activity, including antiviral drugs, antimalarial drugs, immunosuppressants, Chinese medicines, Mpro inhibitors, JAK inhibitors, etc. The most commonly used drugs are antiviral compounds, antimalarial drugs and JAK inhibitors. In this review, we summarize mainly the antimalarial drugs chloroquine and hydroxychloroquine, the antiviral drugs Favipiravir and Remdesivir, and JAK inhibitor Ruxolitinib, discussing their biological activities, clinical trials and synthesis progress.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":675,"name":"Progresses in clinical studies on antiviral therapies for COVID\u201019\u2014Experience and lessons in design of clinical trials","author":"Getu Zhaori, Lu Lu, Chunyan Liu, Yongli Guo","doi":"10.1002\/ped4.12227","abstract":"Antiviral therapy with antiviral agents is a very important component of treatment for the 2019 novel coronavirus disease (COVID\u201019) caused by the severe acute respiratory syndrome coronavirus\u20102 (SARS\u2010CoV\u20102). It is important to clarify how to evaluate efficacy and safety of antiviral agents in treatment of COVID\u201019 during the pandemic of this disease. We need to answer the following questions: do we still need to use rigorously designed randomized controlled clinical trials (RCTs)? Or, will it be enough if we use loosened criteria, observational studies or even retrospective case series and case reports? The answer is \u201cNo, we still need to use the strictly designed preferably blinded multicenter RCTs to evaluate the antiviral agents.\u201d In this article, we reviewed almost all the RCT reports on monotherapies and combined therapies with antiviral agents for COVID\u201019, and found that among the reports on monotherapies, only remdesivir, and among combined antiviral agents, only the combined regimen with interferon\u2010\u03b21b, lopinavir\u2010ritonavir and ribavirin were effective and safe based on evidences from RCTs. The results of five RCTs for chloroquine or hydroxychloroquine consistently showed that they were ineffective and unsafe in the treatment of COVID\u201019, especially at larger doses. Many aspects in the design of the clinical trials may be related to success or failure of a trial and the relevant factors need to be analyzed, discussed and emphasized from the specific requirements and considerations of antiviral therapies. We hope such discussions be of certain use in designing clinical trials for pediatric antiviral therapies.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":674,"name":"Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro, in vivo, and clinical trials","author":"Young Joo Han, Keum Hwa Lee, Sojung Yoon, Seoung Wan Nam, Seohyun Ryu, Dawon Seong, Jae Seok Kim, Jun Young Lee, Jae Won Yang, Jinhee Lee, Ai Koyanagi, Sung Hwi Hong, Elena Dragioti, Joaquim Radua, Lee Smith, Hans Oh, Ramy Abou Ghayda, Andreas Kronbichler, Maria Effenberger, Daniela Kresse, Sara Denicol\u00f2, Woosun Kang, Louis Jacob, Hanwul Shin, Jae Il Shin","doi":"10.7150\/thno.48342","abstract":"Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19.\r\n\r\nMethods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020.\r\n\r\nResults: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir\/daclatasvir (n = 114), colchicine (n = 140), IFN-\u03b21b (n = 193), and convalescent plasma therapy (n = 126).\r\n\r\nConclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.\r\n\r\nKeywords: COVID-19, therapeutic agent, SARS, MERS, mortality, coronavirus","type":"Review","database":"PMC","created":"2021-05-09"},{"id":673,"name":"Major ongoing clinical trials for COVID-19 treatment and studies currently being conducted or scheduled in Japan","author":"Kyoji Ito, Norio Ohmagari, Ayako Mikami, Wataru Sugiura","doi":"10.35772\/ghm.2020.01034","abstract":"The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health and economies. Currently, hundreds of clinical trials on a wide variety of treatments against COVID-19 are being conducted around the world. Here, we conducted a search for ongoing clinical trials for the treatment of COVID-19 at the clinicaltrials.gov database on April 2, 2020. In total, 48 clinical trials were identified, and of these, 41 trials adopted drug intervention and the other 7 trials utilized biological intervention. The number of trials stratified by a chief country conducting the investigation were 18 in China, 5 in the United States, 4 in Canada, 3 in Italy, 2 in France and Brazil, and 4 trials are being performed multinationally. The drugs utilized in more than one trials were remdesivir (6 trials), lopinavir\/ritonavir (6 trials), hydroxychloroquine (6 trials), interferon (5 trials), methylprednisolone (3 trials), nitric oxide gas (3 trials), oseltamivir (2 trials), arbidol (2 trials), and vitamin C (2 trials). We also described the Japanese trials which are now being conducted or scheduled, utilizing lopinavir\/ritonavir, remdesivir, favipiravir, ciclesonide and nafamostat.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":672,"name":"Recent Clinical Trials on Natural Products and Traditional Chinese Medicine Combating the COVID-19","author":"Shivraj Hariram Nile, Guoyin Kai","doi":"10.1007\/s12088-020-00919-x","abstract":"The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing potentially fatal coronavirus disease-19 (COVID-19), with a significant health and economic burden around the globe. Currently many clinical studies are undergoing but still there is no any specific approved therapy or drug established for effective treatment of COVID-19. This review aimed to analyses various clinical studies which have been registered in www.clinicaltrials.gov and http:\/\/www.chictr.org.cn were registered with natural plant-based medicines and Traditional Chinese medicine (TCM) for discovering effective treatment and prevention of COVID-19. Total 46 and 64 natural drug and TCM interventions were identified which mainly determined the preventive strategies and possible treatments for COVID-19 infection. We identified that most of the clinical trial undergoing on natural compound like heparin and vitamin C as therapeutic agents and immune boosters for against COVID-19. Traditional Chinese medicines and herbal medicines can be effectively used as a preventive therapy against COVID-19 and after successful clinical trials and these potential therapies can be promoted by countries around the world.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":671,"name":"Immunotherapies and immunomodulatory approaches in clinical trials - a mini review","author":" Mohd. Iqbal Yatoo, Zeenat Hamid, Izhar Rather, Qurat Ul Ain Nazir, Riyaz Ahmed Bhat, Abrar Ul Haq, Suhail Nabi Magray, Zulfqar Haq, Ranjit Sah, Ruchi Tiwari, Senthil Kumar Natesan, Muhammad Bilal, Harapan Harapan, Kuldeep Dhama","doi":"10.1080\/21645515.2020.1871295","abstract":"The coronavirus disease (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created havoc worldwide. Due to the non-availability of any vaccine or drugs against COVID-19, immunotherapies involving convalescent plasma, immunoglobulins, antibodies (monoclonal or polyclonal), and the use of immunomodulatory agents to enhance immunity are valuable alternative options. Cell-based therapies including natural killer cells, T cells, stem cells along with cytokines and toll-like receptors (TLRs) based therapies are also being exploited potentially against COVID-19. Future research need to strengthen the field of developing effective immunotherapeutics and immunomodulators with a thrust of providing appropriate, affordable, convenient, and cost-effective prophylactic and treatment regimens to combat global COVID-19 crisis that has led to a state of medical emergency enforcing entire countries of the world to devote their research infrastructure and manpower in tackling this pandemic.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":670,"name":"Will curcumin nanosystems be the next promising antiviral alternatives in COVID-19 treatment trials?","author":"Douglas Dourado, Danielle T. Freire, Daniel T. Pereira, Lucas Amaral-Machado, \u00c9verton N. Alencar, Andr\u00e9 Lu\u00eds Branco de Barros, E. S\u00f3crates T. Egito","doi":"10.1016\/j.biopha.2021.111578","abstract":"The COVID-19 has become of striking interest since the number of deaths is constantly rising all over the globe, and the search for an efficient treatment is more urgent. In light of this worrisome scenario, this opinion review aimed to discuss the current knowledge about the potential role of curcumin and its nanostructured systems on the SARS-CoV-2 targets. From this perspective, this work demonstrated that curcumin urges as a potential antiviral key for the treatment of SARS-CoV-2 based on its relation to the infection pathways. Moreover, the use of curcumin-loaded nanocarriers for increasing its bioavailability and therapeutic efficiency was highlighted. Additionally, the potential of the nanostructured systems by themselves and their synergic action with curcumin on molecular targets for viral infections have been explored. Finally, a viewpoint of the studies that need to be carried out to implant curcumin as a treatment for COVID-19 was addressed.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":669,"name":"Evaluation of the Binding Affinity of Anti-Viral Drugs against Main Protease of SARS-CoV-2 Through a Molecular Docking Study","author":" Milon Mondal, Chandan Sarkar, Sarmin Jamaddar, Abul Bashar Ripon Khalipha, Muhammad Torequl Islam, Azmi Mahafzah, Mohammad S. Mubarak","doi":"10.2174\/1871526520666201207124408","abstract":"Background:Coronavirus disease 2019 (COVID-19) is a life intimidating viral infection caused by a positive sense RNA virus belonging to the Coronaviridae family, named severe acute respiratory distress syndrome coronavirus 2 (SARA-CoV-2). Since its outbreak in December 2019, the pandemic has spread to more than 200 countries, infected more than 26 million, and claimed the lives of more than 800,000 people. As a disease, COVID-19 can lead to severe and occasionally fatal respiratory problems in humans. Infection with this virus is associated with fever, cough, dyspnea, and muscle aches, and it may progress to pneumonia, multiple organ failure, and death. To date, there is no specific antiviral treatment against this virus. However, the main viral protease has been recently discovered and it is regarded as an appropriate target for antiviral agents in the search for treatment of COVID-19, due to its pivotal role in polyproteins processing during viral replication.\r\n\r\nAim: Consequently, this study intends to evaluate the effectiveness of FDA-approved anti-viral drugs against SARA-CoV-2 through a molecular docking study.\r\n\r\nMethods: AutoDock Vina in PyRx platform was used for docking analysis against the main viral protease (Mpro) (PDB ID 6LU7), and Computed Atlas of Surface Topography of proteins (CASTp 3.0) was applied for detecting and characterizing cavities, pockets, and channels of this protein structure.\r\n\r\nResults: Results revealed that among the conventional antiviral drugs, the protease inhibitors, lopinavir, amprenavir, indinavir, maraviroc, saquinavir, and daclatasvir showed high binding affinity and interacted with amino acid residues of the binding site.\r\n\r\nConclusion: In conclusion, protease inhibitors may be effective potential antiviral agents against Mpro to combat SARSCoV-2.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":668,"name":"Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike\u2010ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics","author":"Dr. Maria Gil\u2010Moles, Dr. Uttara Basu, Rolf B\u00fcssing, Henrik Hoffmeister, Sebastian T\u00fcrck, Agnieszka Varchmin, Prof.\u2005Dr. Ingo Ott","doi":"10.1002\/chem.202004112","abstract":"Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti\u2010infective effects have been confirmed. Herein, we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS\u2010CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS\u2010CoV\u20102 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the papain\u2010like protease (PLpro) of SARS\u2010CoV\u20101 and SARS\u2010CoV\u20102, which is a key enzyme in the viral replication. Regarding PLpro from SARS\u2010CoV\u20102, the here reported inhibitors are among the very first experimentally confirmed examples with activity against this target enzyme. Importantly, the activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to remove zinc ions from the labile zinc center of the enzyme. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS\u2010CoV antiviral drugs.","type":"Other","database":"PubMed","created":"2021-05-09"},{"id":667,"name":"Screened antipsychotic drugs inhibit SARS-CoV-2 binding with ACE2 in vitro","author":"Jiayu Lu, Yajing Hou, Shuai Ge, Xiangjun Wang, Jue Wang, Tian Hu, Yuexin Lv, Huaizhen He, Cheng Wang","doi":"10.1016\/j.lfs.2020.118889","abstract":"Aim\r\nThe coronavirus disease 2019 (COVID-19) pandemic has swept the globe and no specific effective drug has been identified. Drug repurposing is a well-known method to address the crisis in a time-critical fashion. Antipsychotic drugs (APDs) have been reported to inhibit DNA replication of hepatitis B virus, measles virus germination, and HIV infection, along with replication of SARS-CoV and MERS-CoV, both of which interact with host cells as SARS-CoV-2.\r\n\r\nMethods\r\nNineteen APDs were screened using ACE2-HEK293T cell membrane chromatography (ACE2-HEK293T\/CMC). Cytotoxicity assay, coronavirus spike pseudotype virus entry assay, surface plasmon resonance, and virtual molecular docking were applied to detect affinity between ACE2 protein and drugs and a potential antiviral property of the screened compounds.\r\n\r\nKey findings\r\nAfter the CMC screening, 8 of the 19 APDs were well-retained on ACE2-HEK293T\/CMC column and showed significant antiviral activities in vitro. Three quarters of them belong to phenothiazine and could significantly inhibit the entrance of coronavirus into ACE2-HEK293T cells. Aother two drugs, aripiprazole and tiapride, exhibited weaker inhibition. We selected five of the drugs for subsequent evaluation. All five showed similar affinity to ACE2 and virtual molecular docking demonstrated they bound with different amino acids respectively on ACE2 which SARS-CoV-2 binds to.\r\n\r\nSignificance\r\nEight APDs were screened for binding with ACE2, five of which demonstrated potential protective effects against SARS-CoV-2 through acting on ACE2. Although the five drugs have a weak ability to block SARS-CoV-2 with a single binding site, they may provide a synergistic effect in adjuvant therapy of COVID-19 infection.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":666,"name":"Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease","author":"Pietro Delre, Fabiana Caporuscio, Michele Saviano, Giuseppe Felice Mangiatordi","doi":"10.3389\/fchem.2020.594009","abstract":"In the absence of an approved vaccine, developing effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals is essential to tackle the current pandemic health crisis due to the coronavirus disease 2019 (COVID-19) spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, in silico repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. We present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multitarget activities (i.e., a desirable polypharmacology profile) for the COVID-19 treatment. A dataset including 688 phase III and 1,702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein\u2013ligand interaction fingerprint similarities, conventional docking scores, and MM-GBSA\u2013binding free energies and allowed the identification of some interesting candidates for further in vitro testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":665,"name":"Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing","author":"Brian Jermain, Patrick O. Hanafin, Yanguang Cao, Adrian Lifschitz, Carlos Lanusse, Gauri G. Rao","doi":"10.1016\/j.xphs.2020.08.024","abstract":"SARS-CoV-2 utilizes the IMP\u03b1\/\u03b21 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-\u03b1 (IMP\u03b1) and IMP\u03b21 subunits as well as dissociating the IMP\u03b1\/\u03b21 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng\/mL, far less than the estimated 1750 ng\/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.","type":"Other","database":"PubMed","created":"2021-05-09"},{"id":664,"name":"What is holding back the development of antiviral metallodrugs? A literature overview and implications for SARS-CoV-2 therapeutics and future viral outbreaks","author":"Raphael E. F. de Paiva, Ant\u00f4nio Mar\u00e7al Neto, Igor A. Santos, Ana C. G. Jardim, Pedro P. Corbid, Fernando R. G. Bergamini","doi":"10.1039\/d0dt02478c","abstract":"In light of the Covid-19 outbreak, this review brings together historical and current literature efforts towards the development of antiviral metallodrugs. Classical compounds such as CTC-96 and auranofin are discussed in depth, as pillars for future metallodrug development. From the recent literature, both cell-based results and biophysical assays against potential viral biomolecule targets are summarized here. The comprehension of the biomolecular targets and their interactions with coordination compounds are emphasized as fundamental strategies that will foment further development of metal-based antivirals. We also discuss other possible and unexplored methods for unveiling metallodrug interactions with biomolecules related to viral replication and highlight the specific challenges involved in the development of antiviral metallodrugs.\r\n\r\n","type":"Review","database":"PubMed","created":"2021-05-09"},{"id":663,"name":"Rationalizing Viral Drug Target Identification Using Computational Approaches : The SARS-CoV-2 Spike Glycoprotein S Case Study","author":"Petr Popov, Pavel Buslaev, Igor Kozlovskii, Mark Zaretskii, Dmitry Karlov, Alexander Morozov","doi":"10.26434\/chemrxiv.13251560.v1","abstract":"COVID-19 emphasized the need for fast reaction tools to fight global biological threats such as viruses. Rapid drug discovery is one of the strategies for efficient social response. The success of a drug discovery campaign critically depends on the selected drug target, and the wrong target nullifies all the efforts to develop a drug. Viral drug target identification is a challenging problem, and computational methods can reduce the number of candidate targets. Here we present a structure-based approach to identify vulnerable regions in viral proteins that comprise drug binding sites. To detect promising binding sites, we take into account protein dynamics, accessibility, and mutability of the binding site, coupled with the putative mechanism of action of a drug. Applying to the SARS-CoV-2 Spike Glycoprotein S, we observed conformation- and oligomer-specific glycan-free binding site that is proximal to the receptor binding domain and comprises topologically important amino acid residues. Molecular dynamics simulations of Spike in complex with drug-like molecules docked into the binding sites revealed shifted equilibrium towards the inactive conformation compared to the ligand-free simulations. Small molecules targeting this binding site could prevent the closed-to-open conformational transition of the Spike protein, thus, allosterically inhibit the interaction with the human angiotensin-converting enzyme 2 receptor.","type":"Research","database":"ChemRxiv","created":"2021-05-09"},{"id":662,"name":"Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model","author":"Yoonjung Choi, Bonggun Shin, Keunsoo Kang, Sungsoo Park, Bo Ram Beck","doi":"10.3390\/v12111325","abstract":"Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with Kd of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a Kd value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":661,"name":"Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach","author":" Adewale Oluwaseun Fadaka, Raphael Taiwo Aruleba , Nicole Remaliah Samantha Sibuyi, Ashwil Klein, Abram Madimabe Madiehe, Mervin Meyer","doi":"10.1080\/07391102.2020.1847197","abstract":"The exponential increase in cases and mortality of coronavirus disease (COVID-19) has called for a need to develop drugs to treat this infection. Using in silico and molecular docking approaches, this study investigated the inhibitory effects of Pradimicin A, Lamivudine, Plerixafor and Lopinavir against SARS-CoV-2 Mpro. ADME\/Tox of the ligands, pharmacophore hypothesis of the co-crystalized ligand and the receptor, and docking studies were carried out on different modules of Schrodinger (2019-4) Maestro v12.2. Among the ligands subjected to ADME\/Tox by QikProp, Lamivudine demonstrated drug-like physico-chemical properties. A total of five pharmacophore binding sites (A3, A4, R9, R10, and R11) were predicted from the co-crystalized ligand and the binding cavity of the SARS-CoV-2 Mpro. The docking result showed that Lopinavir and Lamivudine bind with a higher affinity and lower free energy than the standard ligand having a glide score of \u22129.2\u2009kcal\/mol and \u22125.3\u2009kcal\/mol, respectively. Plerixafor and Pradimicin A have a glide score of \u22123.7\u2009kcal\/mol and \u22122.4\u2009kcal\/mol, respectively, which is lower than the co-crystallized ligand with a glide score of \u22125.3\u2009kcal\/mol. Molecular dynamics confirmed that the ligands maintained their interaction with the protein with lower RMSD fluctuations over the trajectory period of 100 nsecs and that GLU166 residue is pivotal for binding. On the whole, present study specifies the repurposing aptitude of these molecules as inhibitors of SARS-CoV-2 Mpro with higher binding scores and forms energetically stable complexes with Mpro.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":660,"name":"Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease","author":"Eduardo Tejera, Cristian R. Munteanu, Andr\u00e9s L\u00f3pez-Cort\u00e9s, Alejandro Cabrera-Andrade, Yunierkis P\u00e9rez-Castillo","doi":"10.3390\/molecules25215172","abstract":"Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure\u2013Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (Mpro) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the Mpro of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the Mpro enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":659,"name":"Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19 ","author":" Krishnaprasad Baby, Swastika Maity, Chetan H. Mehta, Akhil Suresh, Usha Y. Nayak, Yogendra Nayak","doi":"10.12688\/f1000research.26359.1","abstract":"Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (Mpro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV.\r\nMethods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing.\r\nResults: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium.\r\nConclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.\r\n","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":658,"name":"Imatinib is not a potent anti-SARS-CoV-2 drug","author":"Helong Zhao, Michelle Mendenhall, Michael W. Deininger","doi":"10.1038\/s41375-020-01045-9","abstract":"Imatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) used to treat chronic myeloid leukemia (CML), was reported to inhibit infection of SARS-CoV, the coronavirus responsible for the 2003 SARS outbreak, and MERS-CoV, the cause of Middle East Respiratory Syndrome, in cell culture assays [1,2,3]. Mechanistic studies suggested that SARS-CoV relies on ABL2 kinase activity to infect host cells and that inhibiting ABL2 with imatinib blocks coronavirus entry via preventing viral fusion with the cell membrane [1, 2]. Since the SARS-CoV-2 genome is ~80% homologous to that of SARS-CoV [4] and both viruses use host cell ACE2 protein as receptors [5], it is plausible that imatinib also has anti-SARS-CoV-2 activity. Moreover, imatinib was identified as a leading hit from a large-scale drug screening for SARS-CoV-2 protease inhibitors using the Reframe library of clinical and near-clinical compounds [6]. These data suggest that imatinib may have anti-SARS-CoV-2 activity, either on-target through inhibition of ABL1\/2 or off-target through a previously unrecognized protease-inhibiting effect. Although the precise mechanism remains unclear, these data provide a rationale for testing imatinib as an antiviral against COVID-19 in clinical trials. Three prospective randomized clinical trials are underway to study the therapeutic efficacy of imatinib vs. standard of care or placebo in patients with COVID-19, including NCT04357613 (France), NCT04394416 (USA), and EudraCT2020-001236-10 (The Netherlands). However, the anti-SARS-CoV-2 efficacy of imatinib in a standard viral replication assay has not been demonstrated.","type":"Other","database":"PubMed","created":"2021-05-09"},{"id":657,"name":"Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 Main Protease complexes reveal the role of a lateral pocket in enhancing the ligand affinity","author":"Ying Li Weng, Shiv Rakesh Naik, Nadia Dingelstad, Subha Kalyaanamoorthy, Aravindhan Ganesan","doi":"10.1101\/2020.10.31.363309","abstract":"The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand bound Mpro complexes in the protein data bank (PDB) that describe structural details of different chemotypes of fragments binding within different sites in Mpro. In this work, we perform rigorous molecular dynamics (MD) simulation of 62 reversible ligand-Mpro complexes in the PDB to gain mechanistic insights about their interactions at atomic level. Using a total of ~2.25 \u03bcs long MD trajectories, we identified and characterized different pockets and their conformational dynamics in the apo Mpro structure. Later, using the published PDB structures, we analyzed the dynamic interactions and binding affinity of small ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets in Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in this lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":656,"name":"Mechanism of ligand recognition by human ACE2 receptor","author":"Apurba Bhattarai, Shristi Pawnikar, Yinglong Miao","doi":"10.1101\/2020.10.30.362749","abstract":"Angiotensin converting enzyme 2 (ACE2) plays a key role in renin-angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2. ACE2 is also widely expressed in epithelial cells of lungs, heart, kidney and pancreas. It is considered an important drug target for treating SARS-CoV-2, as well as pulmonary diseases, heart failure, hypertension, renal diseases and diabetes. Despite the critical importance, the mechanism of ligand binding to the human ACE2 receptor remains unknown. Here, we address this challenge through all-atom simulations using a novel ligand Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond LiGaMD simulations have successfully captured both binding and unbinding of the MLN-4760 inhibitor in the ACE2 receptor. In the ligand unbound state, the ACE2 receptor samples distinct Open, Partially Open and Closed conformations. Ligand binding biases the receptor conformational ensemble towards the Closed state. The LiGaMD simulations thus suggest a conformational selection mechanism for ligand recognition by the ACE2 receptor. Our simulation findings are expected to facilitate rational drug design of ACE2 against coronaviruses and other related human diseases.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":655,"name":"Discovery of potent inhibitors for SARS-CoV-2's main protease by ligand-based\/structure-based virtual screening, MD simulations, and binding energy calculations","author":"Abd Al-Aziz A. Abu-Saleh, Ibrahim E. Awad, Arpita Yadav, Raymond A. Poirier","doi":"10.1039\/d0cp04326e","abstract":"COVID-19 has caused lockdowns all over the world in early 2020, as a global pandemic. Both theoretical and experimental efforts are seeking to find an effective treatment to suppress the virus. In silico drug design can play a vital role in identifying promising drug candidates against COVID-19. Herein, we focused on the main protease of SARS-CoV-2 that has crucial biological functions in the virus. We performed a ligand-based virtual screening followed by a docking screening for testing approved drugs and bioactive compounds listed in the DrugBank and ChEMBL databases. The top 8 docking results were advanced to all-atom MD simulations to study the relative stability of the protein\u2013ligand interactions. MD simulations support that the catalytic residue, His41, has a neutral side chain with a protonated delta position. An absolute binding energy (\u0394G) of \u221242 kJ mol\u22121 for the protein\u2013ligand (Mpro-N3) complex has been calculated using the potential-of-mean-force (geometrical) approach. Furthermore, the relative binding energies were computed for the top docking results. Our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 Mpro as follows: a bioactive compound, ChEMBL275592, which has the best MM\/GBSA binding energy; the second-best compound, montelukast, is an approved drug used in the treatment of asthma and allergic rhinitis; the third-best compound, ChEMBL288347, is a bioactive compound. Bromocriptine and saquinavir are other approved drugs that also demonstrate stability in the active site of Mpro, albeit their relative binding energies are low compared to the N3 inhibitor. This study provides useful insights into de novo protein design and novel inhibitor development, which could reduce the cost and time required for the discovery of a potent drug to combat SARS-CoV-2.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":654,"name":"Profiling SARS-CoV-2 Main Protease (MPRO) Binding to Repurposed Drugs Using Molecular Dynamics Simulations in Classical and Neural Network-Trained Force Fields","author":"Aayush Gupta, Huan-Xiang Zhou","doi":"10.1021\/acscombsci.0c00140","abstract":"The current COVID-19 pandemic caused by a novel coronavirus SARS-CoV-2 urgently calls for a working therapeutic. Here, we report a computation-based workflow for efficiently selecting a subset of FDA-approved drugs that can potentially bind to the SARS-CoV-2 main protease MPRO. The workflow started with docking (using Autodock Vina) each of 1615 FDA-approved drugs to the MPRO active site. This step selected 62 candidates with docking energies lower than \u22128.5 kcal\/mol. Then, the 62 docked protein\u2013drug complexes were subjected to 100 ns of molecular dynamics (MD) simulations in a molecular mechanics (MM) force field (CHARMM36). This step reduced the candidate pool to 26, based on the root-mean-square-deviations (RMSDs) of the drug molecules in the trajectories. Finally, we modeled the 26 drug molecules by a pseudoquantum mechanical (ANI) force field and ran 5 ns hybrid ANI\/MM MD simulations of the 26 protein\u2013drug complexes. ANI was trained by neural network models on quantum mechanical density functional theory (wB97X\/6-31G(d)) data points. An RMSD cutoff winnowed down the pool to 12, and free energy analysis (MM\/PBSA) produced the final selection of 9 drugs: dihydroergotamine, midostaurin, ziprasidone, etoposide, apixaban, fluorescein, tadalafil, rolapitant, and palbociclib. Of these, three are found to be active in literature reports of experimental studies. To provide physical insight into their mechanism of action, the interactions of the drug molecules with the protein are presented as 2D-interaction maps. These findings and mappings of drug\u2013protein interactions may be potentially used to guide rational drug discovery against COVID-19.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":653,"name":"The Binding of Remdesivir to SARS-CoV-2 RNA-Dependent RNA polymerase May Pave The Way Towards the Design of Potential Drugs for COVID-19 Treatment","author":"Clement Agoni, Mahmoud E.S. Soliman","doi":"10.2174\/1389201021666201027154833","abstract":"Aim: We seek to provide an understanding of the binding mechanism of Remdesivir, provide structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties.\r\n\r\nBackground: The coronavirus disease of 2019 (COVID-19) pandemic has infected over a million people, with over 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline so far is Remdesivir.\r\n\r\nObjectives: We perform molecular dynamics simulation, quantify the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generate a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors.\r\n\r\nMethods: Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced postmolecular dynamics analysis techniques were employed.\r\n\r\nResults: Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of highaffinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding, induces minimal individual amino acid perturbations, subtly interferes with deviations of C-\u03b1 atoms and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the \u201cburied\u201d hydrophobic region to the \u201csurface-exposed\u201d hydrophilic region. We also mapped a pharmacophore model based on observed high-affinity interactions with SARS-CoV-2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening.\r\n\r\nConclusion: The structural insights and the optimized pharmacophoric model provided would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":652,"name":"Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)","author":"Sehrish Bano, Abdul Hameed, Mariya Al-Rashida, Shafia Iftikhar, Jamshed Iqbal","doi":" 10.2174\/0929867327666201027153617","abstract":"Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents.\r\n\r\nObjective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules.\r\n\r\nMethods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP.\r\n\r\nResults: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus.\r\n\r\nConclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.","type":"Review","database":"PubMed","created":"2021-05-09"},{"id":651,"name":"Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19","author":"Brian L. Le, Gaia Andreoletti, Tomiko Oskotsky, Albert Vallejo-Gracia, Romel Rosales, Katharine Yu, Idit Kosti, Kristoffer E. Leon, Daniel G. Bunis, Christine Li, G. Renuka Kumar, Kris M. White, Adolfo Garc\u00eda-Sastre, Melanie Ott, Marina Sirota","doi":"10.1101\/2020.10.23.352666","abstract":"The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated sixteen of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":650,"name":"Computational and theoretical exploration for clinical suitability of Remdesivir drug to SARS-CoV-2","author":"Shaik Mahammad Nayeem,Ershad Mohammed Sohail, Gajjela Priyanka Sudhir, Munnangi Srinivasa Reddy","doi":"10.1016\/j.ejphar.2020.173642","abstract":"A methodology for the exploration of clinical suitability of Remdesivir drug to SARS-CoV-2 main protease based on the computational, theoretical analysis pertinent to Gibb's free energy computed from the Molecular Dynamic simulations with OPLS-AA force field at 300 K\/atmospheric pressure and the variation of thermodynamic potentials over the entire simulation run of 100 ns. This study emphasized the suitability of Remdesivir drug to SARS-CoV-2 protein and the same is emphasized by the results of global clinical trials. This methodology can be applied for future design, development of more specific repurposed inhibitors for the treatment of SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":649,"name":"Repurposing anticancer drugs for the management of COVID-19","author":" Khalid El Bairi, Dario Trapani, Angelica Petrillo, C\u00e9cile Le Page, Hanaa Zbakh, Bruno Daniele, Rhizlane Belbaraka, Giuseppe Curigliano, Said Afqir","doi":"10.1016\/j.ejca.2020.09.014","abstract":"Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion and thus is regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been largely applied for early clinical testing. In this review, we discuss some repurposed anticancer drugs for the treatment of COVID-19, which are under investigation in clinical trials or proposed for the clinical testing.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":648,"name":"Pentoxifylline: A Drug with Antiviral and Anti-Inflammatory Effects to Be Considered in the Treatment of Coronavirus Disease 2019","author":"Ghasemnejad-Berenji M, Pashapour S,  Sadeghpour S","doi":"doi.org\/10.1159\/000512234","abstract":"In December 2019, a new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged from China, causing pneumonia outbreaks first in the Wuhan region and has now spread worldwide. There are no specific drugs for the disease caused by this virus, coronavirus disease 2019 (COVID-19). Considering that new synthesized drugs cannot be applied immediately to patients, conventional drug in new use is a feasible solution. Chloroquine, remdesivir, favipiravir, lopinavir, ribavirin, and ritonavir have shown efficacy to inhibit coronavirus in vitro. Pentoxifylline, a drug with anti-inflammatory, immunomodulatory, and bronchodilatory effects, has previously been shown to inhibit several viral infections. Immunological studies have shown that most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines. Pentoxifylline is a phosphodiesterase inhibitor that increases the levels of cyclic adenosine monophosphate, which in turn activates protein kinase, leading to a reduction in the synthesis of pro-inflammatory cytokines and immune cell migration. Here, we propose pentoxifylline, a drug with low cost and toxicity, as a possible treatment for COVID-19 based on its interesting properties.","type":"Other","database":"PubMed","created":"2021-05-09"},{"id":647,"name":"Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells","author":"Xammy Nguyenla, Eddie Wehri, Erik Van Dis, Scott B. Biering, Livia H. Yamashiro, Julien Stroumza, Claire Dugast-Darzacq, Thomas Graham, Sarah Stanley, Julia Schaletzky","doi":"10.1101\/2020.09.18.302398","abstract":"The SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with currently 29 million confirmed cases and close to a million deaths. At this time, there are no FDA-approved vaccines or therapeutics for COVID-19, but Emergency Use Authorization has been granted for remdesivir, a broad-spectrum antiviral nucleoside analog. However, remdesivir is only moderately efficacious against SARS-CoV-2 in the clinic, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. We identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5 A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir\u2019s apparent potency 25-fold. We therefore suggest that the FDA-approved Hepatitis C therapeutics Epclusa (velpatasvir\/sofosbuvir) and Zepatier (elbasvir\/grazoprevir) should be fast-tracked for clinical evaluation in combination with remdesivir to improve treatment of acute SARS-CoV-2 infections.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":645,"name":"Inhaled and systemic heparin as a repurposed direct antiviral drug for prevention and treatment of COVID-19","author":"Carina Conzelmann, Janis A M\u00fcller, Lukas Perkhofer, Konstantin MJ Sparrer, Alexander N Zelikin, Jan M\u00fcnch, Alexander Kleger","doi":"10.7861\/clinmed.2020-0351","abstract":"Here, we advocate a highly favourable opportunity for the treatment of COVID-19 disease by repurposing a long-serving medical agent with an excellent history of clinical use, namely heparin. Heparin is best known as an anticoagulant, but it also exhibits direct antiviral activity against many enveloped viruses and has anti-inflammatory activity. The high incidence of thromboembolic events in COVID-19 patients suggests that coagulopathy plays an important role in the SARS-CoV-2 pathogenesis. This already makes heparin a unique, potentially curative agent that can be used immediately to help resolve the ongoing crisis associated with SARS-CoV-2 infection and COVID-19 disease. We demonstrate here in vitro that heparin does indeed inhibit SARS-CoV-2 infection. The three concurrent modes of activity of heparin (antiviral, anticoagulant and anti-inflammatory) against SARS-CoV-2\/COVID-19 form a unique therapeutic combination. Thus, repurposing of heparin to fight SARS-CoV-2 and COVID-19 appears to be a powerful, readily available measure to address the current pandemic.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":644,"name":"Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2","author":"Catherine Z. Chen, Paul Shinn, Zina Itkin, Richard T. Eastman, Robert Bostwick, Lynn Rasmussen, Ruili Huang, Min Shen, Xin Hu, Kelli M. Wilson, Brianna Brooks, Hui Guo, Tongan Zhao, Carleen Klump-Thomas, Anton Simeonov, Samuel G. Michael, Donald C. Lo, Matthew D. Hall, Wei Zheng","doi":"10.1101\/2020.08.18.255877","abstract":"Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":643,"name":"In silico Potential of Approved Antimalarial Drugs for Repurposing Against COVID-19","author":"Cheryl Sachdeva, Anju Wadhwa, Anita Kumari, Firasat Hussain, Preeti Jha, Naveen K. Kaushik","doi":"10.1089\/omi.2020.0071","abstract":"Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2\u2013specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schr\u00f6dinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":642,"name":"Identification of promising drug candidates against NSP16 of SARS-CoV-2 through computational drug repurposing study","author":" Viswanathan Vijayan, Pradeep Pant, Naval Vikram, Punit Kaur, T. P. Singh, Sujata Sharma, Pradeep Sharma ","doi":"10.1080\/07391102.2020.1802349","abstract":"The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19, a global pandemic has resulted in an unprecedented loss of life and economy worldwide. Hence, there is an urgent need to discover effective drugs to control this pandemic. NSP16 is a methyltransferase that methylates the ribose 2\u2032-O position of the viral nucleotide. Taking advantage of the recently solved structure of NSP16 with its inhibitor, S-Adenosylmethionine, we have virtually screened FDA approved drugs, drug candidates and natural compounds. The compounds with the best docking scores were subjected to molecular dynamics simulations followed by binding free energy calculations using the MM-PBSA method. The known drugs which were identified as potential inhibitors of NSP16 from SARS-CoV-2 included DB02498, DB03909, DB03186, Galuteolin, ZINC000029416466, ZINC000026985532, and ZINC000085537017. DB02498 (Carba-nicotinamide-adenine-dinucleotide) is an approved drug which has been used since the late 1960s in intravenous form to significantly lessen withdrawal symptoms from a variety of drugs and alcohol addicts and it has the best MM-PBSA binding free energy of\u201312.83\u2009\u00b1\u20090.52\u2009kcal\/mol. The second best inhibitor, Galuteolin is a natural compound that inhibits tyrosinase enzyme with MM-PBSA binding free energy value of \u221211.21\u2009\u00b1\u20090.47\u2009kcal\/mol. Detailed ligand and protein interactions were analyzed and common residues across SARS-CoV, SARS-CoV-2, and MERS-CoV were identified. We propose Carba-nicotinamide-adenine-dinucleotide and Galuteolin as the potential inhibitors of NSP16. The results in this study can be used for the treatment of COVID-19 and can also form the basis of rational drug design against NSP16 of SARS-CoV-2.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":641,"name":"In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy","author":"Tian-zi Wei, Hao Wang, Xue-qing Wu, Yi Lu, Sheng-hui Guan, Feng-quan Dong, Chen-le Dong, Gu-li Zhu, Yu-zhou Bao, Jian Zhang, Guan-yu Wang & Hai-ying Li","doi":"10.1007\/s11655-020-3427-6","abstract":"Objective\r\nTo select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.\r\n\r\nMethods\r\nThe three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.\r\n\r\nResults\r\nIt was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (\u83b2\u82b1\u6e05\u761f), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.\r\n\r\nConclusions\r\nA class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":640,"name":"Discovery of Potent SARS-CoV-2 Inhibitors from Approved Antiviral Drugs via Docking and Virtual Screening","author":"Samir Chtita, Assia Belhassan, Adnane Aouidate, Salah Belaidi, Mohammed Bouachrine, Tahar Lakhlifi","doi":"10.2174\/1386207323999200730205447","abstract":"Background: Coronavirus Disease 2019 (COVID-19) pandemic continues to threaten patients, societies and healthcare systems around the world. There is an urgent need to search for possible medications.\r\n\r\nObjective: This article intends to use virtual screening and molecular docking methods to find potential inhibitors from existing drugs that can respond to COVID-19.\r\n\r\nMethods: To take part in the current research investigation and to define a potential target drug that may protect the world from the pandemic of corona disease, a virtual screening study of 129 approved drugs was carried out which showed that their metabolic characteristics, dosages used, potential efficacy and side effects are clear as they have been approved for treating existing infections. Especially 12 drugs against chronic hepatitis B virus, 37 against chronic hepatitis C virus, 37 against human immunodeficiency virus, 14 anti-herpesvirus, 11 anti-influenza, and 18 other drugs currently on the market were considered for this study. These drugs were then evaluated using virtual screening and molecular docking studies on the active site of the (SARS-CoV-2) main protease (6lu7). Once the efficacy of the drug is determined, it can be approved for its in vitro and in vivo activity against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can be beneficial for the rapid clinical treatment of patients.\r\n\r\nThese drugs were considered potentially effective against SARS-CoV-2 and those with high molecular docking scores were proposed as novel candidates for repurposing. The N3 inhibitor cocrystallized with protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison.\r\n\r\nResults: The results suggest the effectiveness of Beclabuvir, Nilotinib, Tirilazad, Trametinib and Glecaprevir as potent drugs against SARS-CoV-2 since they tightly bind to its main protease.\r\n\r\nConclusion: These promising drugs can inhibit the replication of the virus; hence, the repurposing of these compounds is suggested for the treatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs requires further in vivo tests of these drugs.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":639,"name":"In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression","author":"Sanju Sinha, Kuoyuan Cheng, Alejandro A Sch\u00e4ffer, Kenneth Aldape, Eyal Schiff, Eytan Ruppin","doi":"10.15252\/msb.20209628","abstract":"The COVID\u201019 pandemic caused by SARS\u2010CoV\u20102 has been a global health challenge. Angiotensin\u2010converting enzyme 2 (ACE2) is the host receptor for SARS\u2010CoV\u20102 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID\u201019 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2\u2010upregulating drugs, while antineoplastic agents are enriched for ACE2\u2010downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up\/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID\u201019, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.","type":"Other","database":"PubMed","created":"2021-05-09"},{"id":637,"name":"Drug Discovery Strategies for SARS-CoV-2","author":"Zeenat A. Shyr, Kirill Gorshkov, Catherine Z. Chen and Wei Zheng","doi":"10.1124\/jpet.120.000123","abstract":"Coronavirus disease 2019 (COVID-19) is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus that was first detected in December of 2019 in Wuhan, China, and has rapidly spread worldwide. The search for a suitable vaccine as well as effective therapeutics for the treatment of COVID-19 is underway. Drug repurposing screens provide a useful and effective solution for identifying potential therapeutics against SARS-CoV-2. For example, the experimental drug remdesivir, originally developed for Ebola virus infections, has been approved by the US Food and Drug Administration as an emergency use treatment of COVID-19. However, the efficacy and toxicity of this drug need further improvements. In this review, we discuss recent findings on the pathology of coronaviruses and the drug targets for the treatment of COVID-19. Both SARS-CoV-2\u2013specific inhibitors and broad-spectrum anticoronavirus drugs against SARS-CoV, Middle East respiratory syndrome coronavirus, and SARS-CoV-2 will be valuable additions to the anti\u2013SARS-CoV-2 armament. A multitarget treatment approach with synergistic drug combinations containing different mechanisms of action may be a practical therapeutic strategy for the treatment of severe COVID-19.","type":"Review","database":"PubMed","created":"2021-05-09"},{"id":636,"name":"Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis","author":"Keunsoo Kang, Hoo Hyun Kim, Yoonjung Choi","doi":"10.3390\/v12070776","abstract":"The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects almost everyone in the world in many ways. We previously predicted antivirals (atazanavir, remdesivir and lopinavir\/ritonavir) and non-antiviral drugs (tiotropium and rapamycin) that may inhibit the replication complex of SARS-CoV-2 using our molecular transformer\u2013drug target interaction (MT\u2013DTI) deep-learning-based drug\u2013target affinity prediction model. In this study, we dissected molecular pathways upregulated in SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells by analyzing an RNA-seq data set with various bioinformatics approaches, such as gene ontology, protein\u2013protein interaction-based network and gene set enrichment analyses. The results indicated that the SARS-CoV-2 infection strongly activates TNF and NF\u03baB-signaling pathways through significant upregulation of the TNF, IL1B, IL6, IL8, NFKB1, NFKB2 and RELB genes. In addition to these pathways, lung fibrosis, keratinization\/cornification, rheumatoid arthritis, and negative regulation of interferon-gamma production pathways were also significantly upregulated. We observed that these pathologic features of SARS-CoV-2 are similar to those observed in patients with chronic obstructive pulmonary disease (COPD). Intriguingly, tiotropium, as predicted by MT\u2013DTI, is currently used as a therapeutic intervention in COPD patients. Treatment with tiotropium has been shown to improve pulmonary function by alleviating airway inflammation. Accordingly, a literature search summarized that tiotropium reduced expressions of IL1B, IL6, IL8, RELA, NFKB1 and TNF in vitro or in vivo, and many of them have been known to be deregulated in COPD patients. These results suggest that COVID-19 is similar to an acute mode of COPD caused by the SARS-CoV-2 infection, and therefore tiotropium may be effective for COVID-19 patients.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":635,"name":"In-silico drug repurposing and molecular dynamics puzzled out potential SARS-CoV-2 main protease inhibitors","author":" Mahmoud A. A. Ibrahim, Alaa H. M. Abdelrahman, Mohamed-Elamir F. Hegazy","doi":"10.1080\/07391102.2020.1791958","abstract":"Herein, the DrugBank database which contains 10,036 approved and investigational drugs was explored deeply for potential drugs that target SARS-CoV-2 main protease (Mpro). Filtration process of the database was conducted using three levels of accuracy for molecular docking calculations. The top 35 drugs with docking scores >\u2009\u221211.0\u2009kcal\/mol were then subjected to 10\u2009ns molecular dynamics (MD) simulations followed by molecular mechanics\u2013generalized Born surface area (MM-GBSA) binding energy calculations. The results showed that DB02388 and Cobicistat (DB09065) exhibited potential binding affinities towards Mpro over 100\u2009ns MD simulations, with binding energy values of \u221249.67 and \u221246.60\u2009kcal\/mol, respectively. Binding energy and structural analyses demonstrated the higher stability of DB02388 over Cobicistat. The potency of DB02388 and Cobicistat is attributed to their abilities to form several hydrogen bonds with the essential amino acids inside the active site of Mpro. Compared to DB02388 and Cobicistat, Darunavir showed a much lower binding affinity of \u221234.83\u2009kcal\/mol. The present study highlights the potentiality of DB02388 and Cobicistat as anti-COVID-19 drugs for clinical trials.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":634,"name":"Antiviral Drug Screen of Kinase inhibitors Identifies Cellular Signaling Pathways Critical for SARS-CoV-2 Replication","author":"Gustavo Garcia Jr., Arun Sharma, Arunachalam Ramaiah, Chandani Sen, Donald Kohn, Brigitte Gomperts, Clive N. Svendsen, Robert D Damoiseaux, Vaithilingaraja Arumugaswami","doi":"10.1101\/2020.06.24.150326","abstract":"Emergence of a highly contagious novel coronavirus, SARS-CoV-2 that causes COVID-19, has precipitated the current global health crisis with over 479,000 deaths and more than 9.3 million confirmed cases. Currently, our knowledge of the mechanisms of COVID-19 disease pathogenesis is very limited which has hampered attempts to develop targeted antiviral strategies. Therefore, we urgently need an effective therapy for this unmet medical need. Viruses hijack and dysregulate cellular machineries in order for them to replicate and infect more cells. Thus, identifying and targeting dysregulated signaling pathways that have been taken over by viruses is one strategy for developing an effective antiviral therapy. We have developed a high-throughput drug screening system to identify potential antiviral drugs targeting SARS-CoV-2. We utilized a small molecule library of 430 protein kinase inhibitors, which are in various stages of clinical trials. Most of the tested kinase antagonists are ATP competitive inhibitors, a class of nucleoside analogs, which have been shown to have potent antiviral activity. From the primary screen, we have identified 34 compounds capable of inhibiting viral cytopathic effect in epithelial cells. Network of drug and protein relations showed that these compounds specifically targeted a limited number of cellular kinases. More importantly, we have identified mTOR-PI3K-AKT, ABL-BCR\/MAPK, and DNA-Damage Response (DDR) pathways as key cellular signaling pathways critical for SARS-CoV-2 infection. Subsequently, a secondary screen confirmed compounds such as Berzosertib (VE-822), Vistusertib (AZD2014), and Nilotinib with anti SARS-CoV-2 activity. Finally, we found that Berzosertib, an ATR kinase inhibitor in the DDR pathway, demonstrated potent antiviral activity in a human epithelial cell line and human induced pluripotent stem cell (hIPSC)-derived cardiomyocytes. These inhibitors are already in clinical trials of phase 2 or 3 for cancer treatment, and can be repurposed as promising drug candidates for a host-directed therapy of SARS-CoV-2 infection. In conclusion, we have identified small molecule inhibitors exhibiting anti SARS-CoV-2 activity by blocking key cellular kinases, which gives insight on important mechanism of host-pathogen interaction. These compounds can be further evaluated for the treatment of COVID-19 patients following additional in vivo safety and efficacy studies.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":633,"name":"Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?","author":"Christian Bailly, G\u00e9rard Vergoten","doi":"10.1016\/j.pharmthera.2020.107618","abstract":"Safe and efficient drugs to combat the current COVID-19 pandemic are urgently needed. In this context, we have analyzed the anti-coronavirus potential of the natural product glycyrrhizic acid (GLR), a drug used to treat liver diseases (including viral hepatitis) and specific cutaneous inflammation (such as atopic dermatitis) in some countries. The properties of GLR and its primary active metabolite glycyrrhetinic acid are presented and discussed. GLR has shown activities against different viruses, including SARS-associated Human and animal coronaviruses. GLR is a non-hemolytic saponin and a potent immuno-active anti-inflammatory agent which displays both cytoplasmic and membrane effects. At the membrane level, GLR induces cholesterol-dependent disorganization of lipid rafts which are important for the entry of coronavirus into cells. At the intracellular and circulating levels, GLR can trap the high mobility group box 1 protein and thus blocks the alarmin functions of HMGB1. We used molecular docking to characterize further and discuss both the cholesterol- and HMG box-binding functions of GLR. The membrane and cytoplasmic effects of GLR, coupled with its long-established medical use as a relatively safe drug, make GLR a good candidate to be tested against the SARS-CoV-2 coronavirus, alone and in combination with other drugs. The rational supporting combinations with (hydroxy)chloroquine and tenofovir (two drugs active against SARS-CoV-2) is also discussed. Based on this analysis, we conclude that GLR should be further considered and rapidly evaluated for the treatment of patients with COVID-19.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":632,"name":"Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets","author":"Mallikarjuna Nimgampalle, Vasudharani Devanathan, Ambrish Saxena","doi":"10.1080\/07391102.2020.1782265","abstract":"Recently Chloroquine and its derivative Hydroxychloroquine have garnered enormous interest amongst the clinicians and health authorities\u2019 world over as a potential treatment to contain COVID-19 pandemic. The present research aims at investigating the therapeutic potential of Chloroquine and its potent derivative Hydroxychloroquine against SARS-CoV-2 viral proteins. At the same time screening was performed for some chemically synthesized derivatives of Chloroquine and compared their binding efficacy with chemically synthesized Chloroquine derivatives through in silico approaches. For the purpose of the study, some essential viral proteins and enzymes were selected that are implicated in SARS-CoV-2 replication and multiplication as putative drug targets. Chloroquine, Hydroxychloroquine, and some of their chemically synthesized derivatives, taken from earlier published studies were selected as drug molecules. We have conducted molecular docking and related studies between Chloroquine and its derivatives and SARS-CoV-2 viral proteins, and the findings show that both Chloroquine and Hydroxychloroquine can bind to specific structural and non-structural proteins implicated in the pathogenesis of SARS-CoV-2 infection with different efficiencies. Our current study also shows that some of the chemically synthesized Chloroquine derivatives can also potentially inhibit various SARS-CoV-2 viral proteins by binding to them and concomitantly effectively disrupting the active site of these proteins. These findings bring into light another possible mechanism of action of Chloroquine and Hydroxychloroquine and also pave the way for further drug repurposing and remodeling.","type":"Research","database":"PubMed","created":"2021-05-09"},{"id":631,"name":"Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2","author":"Mark Dittmar, Jae Seung Lee, Kanupriya Whig, Elisha Segrist, Minghua Li, Kellie Jurado, Kirandeep Samby, Holly Ramage, David Schultz, Sara Cherry","doi":"10.1101\/2020.06.19.161042","abstract":"There are an urgent need for antivirals to treat the newly emerged SARS-CoV-2. To identify new candidates we screened a repurposing library of ~3,000 drugs. Screening in Vero cells found few antivirals, while screening in human Huh7.5 cells validated 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we found that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH-independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we found 9 drugs are antiviral in lung cells, 7 of which have been tested in humans, and 3 are FDA approved including Cyclosporine which we found is targeting Cyclophilin rather than Calcineurin for its antiviral activity. These antivirals reveal essential host targets and have the potential for rapid clinical implementation.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":630,"name":"Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19","author":"Malina A. Bakowski, Nathan Beutler, Emily Chen, Tu-Trinh H. Nguyen, Melanie G. Kirkpatrick, Mara Parren, Linlin Yang, James Ricketts, Anil K. Gupta, Mitchell V. Hull, Peter G. Schultz, Dennis R. Burton, Arnab K. Chatterjee, Case W. McNamara, Thomas F. Rogers","doi":"10.1101\/2020.06.16.153403","abstract":"The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10-deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.","type":"Research","database":"BioRxiv","created":"2021-05-09"},{"id":629,"name":"A high-throughput drug screening strategy against coronaviruses","author":"Jia Liu, Kang Li, Lin Cheng, Jingjin Shao, Shukun Yang, Wei Zhang, Guangqian Zhou, Antoine A.F. de Vries, Zhiyi Yu","doi":"10.1016\/j.ijid.2020.12.033","abstract":"The emergence and re-emergence of coronaviruses (CoV) continually cause circulating epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. The resultant disease, coronavirus disease 2019 (COVID-19), has rapidly developed into a worldwide pandemic, leading to severe health and economic burdens. Although the recently announced vaccines against COVID-19 has rekindled hope, there is still a major challenge to urgently meet the global need for rapid treatment of the pandemic. Given the urgency of the CoV outbreak, we propose a strategy to screen potential broad-spectrum drugs against CoV in a high-throughput manner, particularly against SARS-CoV-2. Since the essential functional domains of CoV are extensively homologous, the availability of two types of mild CoV, HCoV-OC43 and MHV, should provide a valuable tool for the rapid identification of promising drugs against CoV without the drawbacks of level three biological confinements. The luciferase reporter gene is introduced into HCoV-OC43 and MHV to indicate viral activity, and hence the antiviral efficiency of screened drugs can be quantified by luciferase activity. Compounds with antiviral activity against both HCoV-OC43 and MHV are further evaluated in SARS-CoV-2 after structural optimizations. This system allows large-scale compounds to be screened to search for broad-spectrum drugs against CoV in a high-throughput manner, providing potential alternatives for clinical management of SARS-CoV-2 or other CoV.\r\n","type":"Review","database":"PMC","created":"2021-05-09"},{"id":628,"name":"In-silico drug repurposing study: Amprenavir, enalaprilat, and plerixafor, potential drugs for destabilizing the SARS-CoV-2 S-protein-angiotensin-converting enzyme 2 complex","author":"Ivonne Buitr\u00f3n-Gonz\u00e1lez, Giovanny Aguilera-Dur\u00e1n, Antonio Romo-Mancillas","doi":"10.1016\/j.rechem.2020.100094","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that leads to coronavirus disease (COVID-19) has put public health at risk in 2020. The spike protein (SP) in SARS-CoV-2 is primarily responsible for the attachment and entry of the virus into the cell, which binds to the angiotensin-converting enzyme 2 (ACE2). Owing to the lack of an effective therapy, drug repositioning is an opportunity to search for molecules with pharmacological potential for the treatment of COVID-19. In this study, three candidates with the potential to destabilize the SP-ACE2 complex are reported. Through molecular docking, 147 drugs were evaluated and their possible binding sites in the interface region of the SP-ACE2 complex and the SP of SARS-CoV-2 were identified. The five best candidate molecules were selected for molecular dynamics studies to observe changes in interactions between SP-ACE2 and ligands with the SP-ACE2 complex. Using umbrella sampling molecular dynamics simulations, the binding energy of SP with ACE2 (\u221229.58 kcal\/mol) without ligands, and in complex with amprenavir (\u221220.13 kcal\/mol), enalaprilat (\u201323.84 kcal\/mol), and plerixafor (\u221219.72 kcal\/mol) were calculated. These drugs are potential candidates for the treatment of COVID-19 as they destabilize the SP-ACE2 complex; the binding energy of SP is decreased in the presence of these drugs and may prevent the virus from entering the cell. Plerixafor is the drug with the greatest potential to destabilize the SP-ACE2 complex, followed by amprenavir and enalaprilat; thus, these three drugs are proposed for future in vitro and in vivo evaluations.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":627,"name":"Synergistic and Antagonistic Drug Combinations against SARS-CoV-2","author":"Tesia Bobrowski, Lu Chen, Richard T. Eastman, Zina Itkin, Paul Shinn, Catherine Z. Chen, Hui Guo, Wei Zheng, Sam Michael, Anton Simeonov, Matthew D. Hall, Alexey V. Zakharov, Eugene N. Muratov","doi":"10.1016\/j.ymthe.2020.12.016","abstract":"Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2, thus generating better antiviral efficacy. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Sixteen synergistic and eight antagonistic combinations were identified; among 16 synergistic cases, combinations of the US Food and Drug Administration (FDA)-approved drug nitazoxanide with remdesivir, amodiaquine, or umifenovir were most notable, all exhibiting significant synergy against SARS-CoV-2 in a cell model. However, the combination of remdesivir and lysosomotropic drugs, such as hydroxychloroquine, demonstrated strong antagonism. Overall, these results highlight the utility of drug repurposing and preclinical testing of drug combinations for discovering potential therapies to treat COVID-19.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":626,"name":"CSF3 Is a Potential Drug Target for the Treatment of COVID-19","author":"Fang Chao, Mei Jie, Tian Huixiang, Liou Yu-Ligh, Rong Dingchao, Zhang Wei, Liao Qianjin, Wu Nayiyuan","doi":"10.3389\/fphys.2020.605792","abstract":"Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious disease that appeared at the end of 2019. As of July 2020, the cumulative number of infections and deaths have exceeded 15 million and 630,000, respectively. And new cases are increasing. There are still many difficulties surrounding research on the mechanism and development of therapeutic vaccines. It is urgent to explore the pathogenic mechanism of viruses to help prevent and treat COVID-19. In our study, we downloaded two datasets related to COVID-19 (GSE150819 and GSE147507). By analyzing the high-throughput expression matrix of uninfected human bronchial organoids and infected human bronchial organoids in the GSE150819, 456 differentially expressed genes (DEGs) were identified, which were mainly enriched in the cytokine\u2013cytokine receptor interaction pathway and so on. We also constructed the protein\u2013protein interaction (PPI) network of DEGs to identify the hub genes. Then we analyzed GSE147507, which contained lung adenocarcinoma cell lines (A549 and Calu3) and the primary bronchial epithelial cell line (NHBE), obtaining 799, 460, and 46 DEGs, respectively. The results showed that in human bronchial organoids, A549, Calu3, and NHBE samples infected with SARS-CoV-2, only one upregulated gene CSF3 was identified. Interestingly, CSF3 is one of the hub genes we previously screened in GSE150819, suggesting that CSF3 may be a potential drug target. Further, we screened potential drugs targeting CSF3 by MOE; the top 50 drugs were screened by flexible docking and rigid docking, with 37 intersections. Two antiviral drugs (Elbasvir and Ritonavir) were included; Elbasvir and Ritonavir formed van der Waals (VDW) interactions with surrounding residues to bind with CSF3, and Elbasvir and Ritonavir significantly inhibited CSF3 protein expression.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":625,"name":"Anti-Inflammation, Immunomodulation and Therapeutic Repair in Current Clinical Trials for the Management of COVID-19","author":"Li C, Zhao H, Cheng L, Wang B","doi":"10.2147\/DDDT.S301173","abstract":"The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to spread around the world. While prophylactic vaccines against SARS-CoV-2 are making great progress, there is still a need to explore safe and effective therapies with biological products for COVID-19. Currently clinical trial efforts are planned and ongoing using different biological agents for anti-inflammatory therapies, immunomodulation, and therapeutic repair in COVID-19. Targeting inflammatory cytokines with antibodies or inhibitors may be an urgent therapeutic strategy for COVID-19. Importantly, it is critical for an in-depth understanding of these new clinical therapeutic agents in their conditions that are probably involved in both physiological and pathological host responses. In this article, we analyze the potential implications for the current clinical trials of therapeutic biologics and address issues for the development of the COVID-19-related biological therapies.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":624,"name":"Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen","author":"Rodon Jordi, Mu\u00f1oz-Basagoiti Jordana, Perez-Zsolt Daniel, Noguera-Julian Marc, Paredes Roger, Mateu Lourdes, Qui\u00f1ones Carles, Perez Carles, Erkizia Itziar, Blanco Ignacio, Valencia Alfonso, Guallar V\u00edctor, Carrillo Jorge, Blanco Juli\u00e0, Segal\u00e9s Joaquim, Clotet Bonaventura, Vergara-Alert J\u00falia, Izquierdo-Useros Nuria","doi":"10.3389\/fphar.2021.646676","abstract":"There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC50 below 25 \u00b5M or 102 IU\/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell\u2014type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":623,"name":"Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development","author":"Miao-Miao Zhao, Wei-Li Yang, Fang-Yuan Yang, Li Zhang, Wei-Jin Huang, Wei Hou, Chang-Fa Fan, Rong-Hua Jin, Ying-Mei Feng, You-Chun Wang, Jin-Kui Yang ","doi":"10.1038\/s41392-021-00558-8","abstract":"To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":622,"name":"SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome","author":"Anna Maria Sardanelli, Camilla Isgr\u00f2, Luigi Leonardo Palese","doi":"10.3390\/molecules26051409","abstract":"In late 2019, a global pandemic occurred. The causative agent was identified as a member of the Coronaviridae family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we present an analysis on the substances identified in the human metabolome capable of binding the active site of the SARS-CoV-2 main protease (Mpro). The substances present in the human metabolome have both endogenous and exogenous origins. The aim of this research was to find molecules whose biochemical and toxicological profile was known that could be the starting point for the development of antiviral therapies. Our analysis revealed numerous metabolites\u2014including xenobiotics\u2014that bind this protease, which are essential to the lifecycle of the virus. Among these substances, silybin, a flavolignan compound and the main active component of silymarin, is particularly noteworthy. Silymarin is a standardized extract of milk thistle, Silybum marianum, and has been shown to exhibit antioxidant, hepatoprotective, antineoplastic, and antiviral activities. Our results\u2014obtained in silico and in vitro\u2014prove that silybin and silymarin, respectively, are able to inhibit Mpro, representing a possible food-derived natural compound that is useful as a therapeutic strategy against COVID-19.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":621,"name":"Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach","author":"Sinead M. O\u2019Donovan, Ali Imami, Hunter Eby, Nicholas D. Henkel, Justin Fortune Creeden, Sophie Asah, Xiaolu Zhang, Xiaojun Wu, Rawan Alnafisah, R. Travis Taylor, James Reigle, Alexander Thorman, Behrouz Shamsaei, Jarek Meller, Robert E. McCullumsmith ","doi":"10.1038\/s41598-021-84044-9","abstract":"The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an \u201comics\u201d repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":620,"name":"Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor","author":"Tamim Ahsana, Abu Ashfaqur Sajib","doi":"10.1016\/j.bbrep.2021.100982","abstract":"Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and\/or ACE1 and potentially interfere with the entry of SARS-CoV-2 inside the host cells.","type":"Research","database":"PMC","created":"2021-05-09"},{"id":619,"name":"Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19","author":"Barbara Malinowska, Marta Baranowska-Kuczko, Aleksandra Kicman, Eberhard Schlicker","doi":"10.3390\/ijms22041986","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with \u03949-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19. View Full-Text","type":"Review","database":"PMC","created":"2021-05-09"},{"id":618,"name":"Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication","author":"Gustavo Garcia Jr., Arun Sharma, Arunachalam Ramaiah, Chandani Sen, Arunima Purkayastha, Donald B. Kohn, Mark S. Parcells, Sebastian Beck, Heeyoung Kim, Malina A. Bakowski, Melanie G. Kirkpatrick, Laura Riva, Karen C. Wolff, Brandon Han, Constance Yuen, David Ulmert, Prabhat K. Purbey, Phillip Scumpia, Nathan Beutler, Thomas F. Rogers, Arnab K. Chatterjee, G\u00fclsah Gabriel, Ralf Bartenschlager, Brigitte Gomperts, Clive N. Svendsen, Ulrich A.K. Betz, Robert D. Damoiseaux, Vaithilingaraja Arumugaswa","doi":"https:\/\/doi.org\/10.1016\/j.celrep.2021.108940","abstract":"SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR\/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.","type":"Other","database":"PMC","created":"2021-05-09"},{"id":617,"name":"Human coronaviruses and therapeutic drug discovery","author":"Lan-Gui Song, Qing-Xing Xie, Hui-Lin Lao, Zhi-Yue Lv ","doi":"10.1186\/s40249-021-00812-9","abstract":"Background\r\nCoronaviruses (CoVs) are distributed worldwide and have various susceptible hosts; CoVs infecting humans are called human coronaviruses (HCoVs). Although HCoV-specific drugs are still lacking, many potent targets for drug discovery are being explored, and many vigorously designed clinical trials are being carried out in an orderly manner. The aim of this review was to gain a comprehensive understanding of the current status of drug development against HCoVs, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).\r\n\r\nMain text\r\nA scoping review was conducted by electronically searching research studies, reviews, and clinical trials in PubMed and the CNKI. Studies on HCoVs and therapeutic drug discovery published between January 2000 and October 2020 and in English or Chinese were included, and the information was summarized. Of the 3248 studies identified, 159 publication were finally included. Advances in drug development against HCoV, especially SARS-CoV-2, are summarized under three categories: antiviral drugs aimed at inhibiting the HCoV proliferation process, drugs acting on the host's immune system, and drugs derived from plants with potent activity. Furthermore, clinical trials of drugs targeting SARS-CoV-2 are summarized.\r\n\r\nConclusions\r\nDuring the spread of COVID-19 outbreak, great efforts have been made in therapeutic drug discovery against the virus, although the pharmacological effects and adverse reactions of some drugs under study are still unclear. However, well-designed high-quality studies are needed to further study the effectiveness and safety of these potential drugs so as to provide valid recommendations for better control of the COVID-19 pandemic.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":616,"name":"Perspectives on plant flavonoid quercetin-based drugs for novel SARS-CoV-2","author":"Manjesh Saakre, Deepu Mathew, V. Ravisankar ","doi":"10.1186\/s43088-021-00107-w","abstract":"Background\r\nThe world pandemic COVID-19 caused by SARS-CoV-2 is currently claiming thousands of lives. Flavonoids abundantly present in the fruits and vegetables, especially quercetin, are shown to have antiviral activities.\r\n\r\nMain text\r\nThis paper reviews the capability of the plant flavonoid quercetin to fight the novel coronavirus and the possibility for drug development based on this. The mode of action explaining the known pathways through which this molecule succeeds in the antiviral activity, action of quercetin on SARS-CoV-2 main protease 3CLpro, antiviral activities of its derivatives on human viruses, effect of combination of zinc co-factor along with quercetin in the COVID-19 treatment, and the regulation of miRNA genes involved in the viral pathogenesis are discussed. Proof for this concept is provided following the virtual screening using ten key enzymes of SARS-CoV-2 and assessing their interactions. Active residues in the 3D structures have been predicted using CASTp and were docked against quercetin. Key proteins 3CLpro, spike glycoprotein\/ human ACE2-BOAT1 complex, RNA-dependent RNA polymerase, main peptidase, spike glycoprotein, RNA replicase, RNA binding protein, papain-like protease, SARS papain-like protease\/ deubiquitinase, and complex of main peptidase with an additional Ala at the N-terminus of each protomer, have shown the binding energies ranging between \u2212 6.71 and \u2212 3.37 kcal\/ Mol, showing that quercetin is a potential drug candidate inhibiting multiple SARS-CoV-2 enzymes.\r\n\r\nConclusion\r\nThe antiviral properties of flavonoid and the molecular mechanisms involved are reviewed. Further, proof for this concept is given by docking of key proteins from SARS-CoV-2 with quercetin.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":615,"name":"Latest updates on SARS-CoV-2 genomic characterization, drug, and vaccine development; a comprehensive bioinformatics review","author":"Masarra M Sakr, Noha S Elsayed, Ghadir S El-Housseiny","doi":"10.1016\/j.micpath.2021.104809","abstract":"Amid the COVID-19 outbreak, several bioinformatic analyses have been conducted on SARS-CoV-2 virus genome. Numerous studies rushed to fill the gap about this novel virus. Comparison with other related sequences, structural predictions of the produced proteins, determination of variations in amino acid residues and depiction of possible drug and vaccine targets have been the focus of scientific research from the beginning of this year. In addition to discussing the viral taxonomy, clinical features, life cycle, and genome organization, this review will focus on the recent updates in genome and viral proteins characterization and potential therapeutic and vaccine candidates developed so far. Comparative studies with related genomes and proteins provide understanding for the viral molecular mechanisms and suggest targets for therapeutics and vaccinology trials to stop the escalation of this new virus. This pandemic, with its resulting social and economic afflictions, will definitely have significant marks on our lives in the following years.","type":"Review","database":"PMC","created":"2021-05-09"},{"id":614,"name":"Rapamycin: Drug Repurposing in SARS-CoV-2 Infection.","author":"Jiri Patocka, Kamil Kuca, Patrik Oleksak, Eugenie Nepovimova, Martin Valis, Michal Novotny, Blanka Klimova","doi":"10.3390\/ph14030217","abstract":"Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world\u2019s acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.","type":"Review","database":"PMC","created":"2021-05-06"},{"id":613,"name":"SARS-CoV-2: Insights into its structural intricacies and functional aspects for drug and vaccine development","author":"Mandeep Kaur, Akanksha Sharma, Santosh Kumar, Gurpal Singh, Ravi P. Barnwala","doi":"10.1016\/j.ijbiomac.2021.02.212","abstract":"Globally, SARS-CoV-2 has emerged as threat to life and economy. Researchers are trying to find a cure against this pathogen but without much success. Several attempts have been made to understand the atomic level details of SARS-CoV-2 in the past few months. However, one review with all structural details for drug and vaccine development has been missing. Hence, this review aims to summarize key functional roles played by various domains of SARS-CoV-2 genome during its entry into the host, replication, repression of host immune response and overall viral life cycle. Additionally, various proteins of SARS-CoV-2 for finding a potent inhibitor have also been highlighted. To mitigate this deadly virus, an understanding of atomic level information, pathogenicity mechanisms and functions of different proteins in causing the infection is imperative. Thus, these structural details would finally pave the way for development of a potential drug\/vaccine against the disease caused by SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-04-26"},{"id":612,"name":"A comprehensive SARS-CoV-2 genomic analysis identifies potential targets for drug repurposing","author":" Nithishwer Mouroug Anand, Devang Haresh Liya, Arpit Kumar Pradhan, Nitish Tayal, Abhinav Bansal, Sainitin Donakonda, Ashwin Kumar Jainarayanan ","doi":"10.1371\/journal.pone.0248553","abstract":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory tract illness. Its higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. One of the major concerns involving the SARS-COV-2 is the mutation rate, which enhances the virus evolution and genome variability, thereby making the design of therapeutics difficult. In this study, we identified the most common haplotypes from the haplotype network. The conserved genes and population level variants were analysed. Non-Structural Protein 10 (NSP10), Nucleoprotein, Papain-like protease (Plpro or NSP3) and 3-Chymotrypsin like protease (3CLpro or NSP5), which were conserved at the highest threshold, were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs, which are suggested for further pre-clinical and clinical trials. This particular study provides a comprehensive targeting of the conserved genes. We also identified the mutation frequencies across the viral genome.","type":"Research","database":"PubMed","created":"2021-04-26"},{"id":611,"name":"Kinetic Characterization and Inhibitor Screening for the Proteases Leading to Identification of Drugs against SARS-CoV-2","author":"Chih-Jung Kuo, Tai-Ling Chao, Han-Chieh Kao, Ya-Min Tsai, Yi-Kai Liu, Lily Hui-Ching Wang, Ming-Chang Hsieh, Sui-Yuan Chang, Po-Huang Liang","doi":"10.1128\/AAC.02577-20","abstract":"Coronavirus (CoV) disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed many lives worldwide and is still spreading since December 2019. The 3C-like protease (3CLpro) and papain-like protease (PLpro) are essential for maturation of viral polyproteins in SARS-CoV-2 life cycle and thus regarded as key drug targets for the disease. In this study, 3CLpro and PLpro assay platforms were established, and their substrate specificities were characterized. The assays were used to screen collections of 1,068 and 2,701 FDA-approved drugs. After excluding the externally used drugs which are too toxic, we totally identified 12 drugs as 3CLpro inhibitors and 36 drugs as PLpro inhibitors active at 10\u2009\u03bcM. Among these inhibitors, six drugs were found to suppress SARS-CoV-2 with the half-maximal effective concentration (EC50) below or close to 10\u2009\u03bcM. This study enhances our understanding on the proteases and provides FDA-approved drugs for prevention and\/or treatment of COVID-19.","type":"Research","database":"PubMed","created":"2021-04-26"},{"id":610,"name":"Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein","author":"Giuseppe Deganutti, Filippo Prischi, Christopher A. Reynolds ","doi":"10.1007\/s10822-020-00356-4","abstract":"The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.","type":"Research","database":"PubMed","created":"2021-04-26"},{"id":609,"name":"In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors","author":"Mahmoud A.A. Ibrahim, Alaa H.M. Abdelrahman, Taha A. Hussien, Esraa A.A. Badr, Tarik A. Mohamed, Hesham R. El-Seedi, Paul W. Pare, Thomas Efferth, Mohamed-Elamir F. Hegazy","doi":"10.1016\/j.compbiomed.2020.104046","abstract":"Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as Mpro inhibitors with binding energies of \u22129.7 and \u22129.2 kcal\/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to Mpro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of \u221244.8, \u221234.2 and \u221234.8 kcal\/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.","type":"Research","database":"PMC","created":"2021-04-26"},{"id":608,"name":"The screening and evaluation of potential clinically significant HIV drug combinations against the SARS-CoV-2 virus","author":"Dra\u0161ko Tomi\u0107, Davor Davidovi\u0107, Attila Marcel Szasz, Melinda Rezeli, Boris Pirki\u0107, Jozsef Petrik, Vesna Ba\u010di\u0107 Vrca, Vladimir Jan\u0111el, Tomislav Lipi\u0107, Karolj Skala, Josip Mesari\u0107, Marija Milkovi\u0107 Peri\u0161a, Zorislav \u0160ojat, Branka Medved Rogina","doi":"10.1016\/j.imu.2021.100529","abstract":"Spike glycoprotein is essential for the reproduction of the SARS-CoV-2 virus, and its inhibition using already approved antiviral drugs may open new avenues for treatment of patients with the COVID-19 disease. Because of that we analyzed the inhibition of SARS-CoV-2 spike glycoprotein with FDA-approved antiviral drugs and their double and triple combinations. We used the VINI in silico model of cancer to perform this virtual drug screening, showing HIV drugs to be the most effective. Besides, the combination of cobicistat-abacavir-rilpivirine HIV drugs demonstrated the highest in silico efficacy of inhibiting SARS-CoV-2 spike glycoprotein. Therefore, a clinical trial of cobicistat-abacavir-rilpivirine on a limited number of COVID-19 patients in moderately severe and severe condition is warranted.","type":"Research","database":"PMC","created":"2021-04-25"},{"id":607,"name":"A Revisit to the Research Updates of Drugs, Vaccines, and Bioinformatics Approaches in Combating COVID-19 Pandemic Tofael Ahmed ","author":"Tofael Ahmed Sumon, Md. Ashraf Hussain, Md. Tawheed Hasan, Mahmudul Hasan, Won Je Jang, Eleus Hussain Bhuiya, Abdullah Al Mamun Chowdhury, S. M. Sharifuzzaman, Christopher Lyon Brown, Hyun-Ju Kwon, Eun-Woo Lee","doi":"10.3389\/fmolb.2020.585899","abstract":"A new strain of coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic was first detected in the city of Wuhan in Hubei province, China in late December 2019. To date, more than 1 million deaths and nearly 57 million confirmed cases have been recorded across 220 countries due to COVID-19, which is the greatest threat to global public health in our time. Although SARS-CoV-2 is genetically similar to other coronaviruses, i.e., SARS and Middle East respiratory syndrome coronavirus (MERS-CoV), no confirmed therapeutics are yet available against COVID-19, and governments, scientists, and pharmaceutical companies worldwide are working together in search for effective drugs and vaccines. Repurposing of relevant therapies, developing vaccines, and using bioinformatics to identify potential drug targets are strongly in focus to combat COVID-19. This review deals with the pathogenesis of COVID-19 and its clinical symptoms in humans including the most recent updates on candidate drugs and vaccines. Potential drugs (remdesivir, hydroxychloroquine, azithromycin, dexamethasone) and vaccines [mRNA-1273; measles, mumps and rubella (MMR), bacille Calmette-Gu\u00e9rin (BCG)] in human clinical trials are discussed with their composition, dosage, mode of action, and possible release dates according to the trial register of US National Library of Medicines (clinicaltrials.gov), European Union (clinicaltrialsregister.eu), and Chinese Clinical Trial Registry (chictr.org.cn) website. Moreover, recent reports on in silico approaches like molecular docking, molecular dynamics simulations, network-based identification, and homology modeling are included, toward repurposing strategies for the use of already approved drugs against newly emerged pathogens. Limitations of effectiveness, side effects, and safety issues of each approach are also highlighted. This review should be useful for the researchers working to find out an effective strategy for defeating SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-04-25"},{"id":606,"name":"Drug discovery and development targeting the life cycle of SARS-CoV-2","author":"Haixia Su, Yechun Xu, Hualiang Jiang","doi":"10.1016\/j.fmre.2021.01.013","abstract":"A newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the \u03b2-coronavirus family and shows high similarities with SARS-CoV. On March 11, 2020, the World Health Organization (WHO) declared SARS-CoV-2 a global pandemic, and the disease was named the coronavirus disease 2019 (COVID-19). The ongoing COVID-19 pandemic has caused over 46 million infections and over one million deaths worldwide, and the numbers are still increasing. Efficacious antiviral agents are urgently needed to combat this virus. The life cycle of SARS-CoV-2 mainly includes the viral attachment, membrane fusion, genomic replication, assembly and budding of virions. Accordingly, drug development against SARS-CoV-2 currently focuses on blocking spike protein binding to ACE2, inhibiting viral membrane fusion with host cells, and preventing the viral replication by targeting 3C-like protease, papain-like protease, RNA-dependent RNA polymerase as well as some host-cell proteins. In this review, the advances of drug development in these three major areas are elaborated.","type":"Review","database":"PMC","created":"2021-04-25"},{"id":605,"name":"Drug Repurposing of Itraconazole and Estradiol Benzoate against COVID\u201019 by Blocking SARS\u2010CoV\u20102 Spike Protein\u2010Mediated Membrane Fusion","author":"Chan Yang,  Xiaoyan Pan,  Yuan Huang,  Chen Cheng,  Xinfeng Xu,  Yan Wu,  Yunxia Xu,  Weijuan Shang,  Xiaoge Niu,  Yihong Wan,  Zhaofeng Li,  Rong Zhang,  Shuwen Liu,  Gengfu Xiao,  Wei Xu","doi":"10.1002\/adtp.202000224","abstract":"SARS\u2010CoV\u20102 caused the emerging epidemic of coronavirus disease in 2019 (COVID\u201019). To date, there are more than 82.9 million confirmed cases worldwide, there is no clinically effective drug against SARS\u2010CoV\u20102 infection. The conserved properties of the membrane fusion domain of the spike (S) protein across SARS\u2010CoV\u20102 make it a promising target to develop pan\u2010CoV therapeutics. Herein, two clinically approved drugs, Itraconazole (ITZ) and Estradiol benzoate (EB), are found to inhibit viral entry by targeting the six\u2010helix (6\u2010HB) fusion core of SARS\u2010CoV\u20102 S protein. Further studies shed light on the mechanism that ITZ and EB can interact with the heptad repeat 1 (HR1) region of the spike protein, to present anti\u2010SARS\u2010CoV\u20102 infections in vitro, indicating they are novel potential therapeutic remedies for COVID\u201019 treatment. Furthermore, ITZ shows broad\u2010spectrum activity targeting 6\u2010HB in the S2 subunit of SARS\u2010CoV and MERS\u2010CoV S protein, inspiring that ITZ have the potential for development as a pan\u2010coronavirus fusion inhibitor.","type":"Research","database":"PubMed","created":"2021-04-25"},{"id":604,"name":"Drug repurposing of nitazoxanide: can it be an effective therapy for COVID-19?","author":"Dina B. Mahmoud, Zayyanu Shitu, Ahmed Mostafa ","doi":"10.1186\/s43141-020-00055-5","abstract":"Background\r\nThe current outbreak of pandemic coronavirus disease 2019 (COVID-19) aggravates serious need for effective therapeutics. Over recent years, drug repurposing has been accomplished as an important opportunity in drug development as it shortens the time consumed for development, besides sparing the cost and the efforts exerted in the research and development process.\r\n\r\nMain body of the abstract\r\nThe FDA-approved antiparasitic drug, nitazoxanide (NTZ), has been found to have antiviral activity against different viral infections such as coronaviruses, influenza, hepatitis C virus (HCV), hepatitis B virus (HBV), and other viruses signifying its potential as a broad spectrum antiviral drug. Moreover, it has been recently reported that NTZ exhibited in vitro inhibition of SARS-CoV-2 at a small micromolar concentration. Additionally, NTZ suppresses the production of cytokines emphasizing its potential to manage COVID-19-induced cytokine storm. Furthermore, the reported efficacy of NTZ to bronchodilate the extremely contracted airways can be beneficial in alleviating COVID-19-associated symptoms.\r\n\r\nShort conclusion\r\nAll these findings, along with the high safety record of the drug, have gained our interest to urge conductance of clinical trials to assess the potential benefits of using it in COVID-19 patients. Thus, in this summarized article, we review the antiviral activities of NTZ and highlight its promising therapeutic actions that make the drug worth clinical trials.","type":"Review","database":"PMC","created":"2021-04-25"},{"id":603,"name":"SARS-CoV-2 RNA Dependent RNA polymerase (RdRp) \u2013 A drug repurposing study","author":"Jamshaid Ahmad ,Saima Ikram ,Fawad Ahmad ,Irshad Ur Rehman ,Maryam Mushtaq","doi":"10.1016\/j.heliyon.2020.e04502","abstract":"The outbreak of SARS-CoV-2 in December 2019 in China subsequently lead to a pandemic. Lack of vaccine and specific anti-viral drugs started a global health disaster. For a sustained control and protection, development of potential anti-viral drugs is one of the targeted approach. Although, designing and developing a panel of new drugs molecules are always encouraged. However, in the current emergency, drug repurposing study is one of the most effective and fast track option. The crystal structure of a SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) RNA Dependent RNA Polymerase (RdRp) has recently been deciphered through X-ray crystallography. The single-chain of core RNA Dependent RNA Polymerase relies on virus-encoded cofactors nsp7 and two units of nsp8 for its optimum function. This study explored the FDA approved database of 7922 molecules and screened against the core polymerase along with cofactors. Here we report a panel of FDA approved drugs that show substantial interactions with key amino acid residues of the active site. Interestingly, some of the identified drugs (Ornipressin, Lypressin, Examorelin, Polymyxin B1) bind strongly within the binding pockets of both forms of RdRp. Besides, we found strong candidates for the complex form as well which include Nacortocin, Cistinexine, Cisatracurium (among others). These drugs have the potential to be considered while contriving therapeutic options.","type":"Research","database":"PMC","created":"2021-04-25"},{"id":602,"name":"In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease","author":"Thrigulla Saketh Ram, Manne Munikumar, Vankudavath Naik Raju, Parasannanavar Devaraj, Naveen Kumar Boiroju, Rajkumar Hemalatha, P.V.V. Prasad, Manohar Gundeti, Brijesh S. Sisodia, Sharad Pawar, G.P. Prasad, Mukesh Chincholikar, Sumeet Goel, Anupam Mangal, Sudesh Gaidhani, N. Srikanth, K.S. Dhiman","doi":"10.1016\/j.jaim.2021.02.004","abstract":"Background\r\nOutbreak of Corona Virus Disease in late 2019 (COVID-19) has become a pandemic global Public health emergency. Since there is no approved anti-viral drug or vaccine declared for the disease and investigating existing drugs against the COVID-19.\r\n\r\nObjective\r\nAYUSH-64 is an Ayurvedic formulation, developed and patented by Central Council of Research in Ayurvedic Sciences, India, has been in clinical use as anti-malarial, anti-inflammatory, anti-pyretic drug for few decades. Thus, the present study was undertaken to evaluate AYUSH-64 compounds available in this drug against Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) Main Protease (Mpro; PDB ID: 6LU7) via in silico techniques.\r\n\r\nMaterials and methods\r\nDifferent molecular docking software\u2019s of Discovery studio and Auto Dock Vina were used for drugs from selected AYUSH-64 compounds against SARS-CoV-2. We also conducted 100 ns period of molecular dynamics simulations with Desmond and further MM\/GBSA for the best complex of AYUSH-64 with Mpro of SARS-CoV-2.\r\n\r\nResults\r\nAmong 36 compounds of four ingredients of AYUSH-64 screened, 35 observed to exhibits good binding energies than the published positive co-crystal compound of N3 pepetide. The best affinity and interactions of Akuammicine N-Oxide (from Alstonia scholaris) towards the Mpro with binding energy (AutoDock Vina) of -8.4 kcal\/mol and Discovery studio of Libdock score of 147.92 kcal\/mol. Further, molecular dynamics simulations with MM-GBSA were also performed for Mpro\u2013 Akuammicine N-Oxide docked complex to identify the stability, specific interaction between the enzyme and the ligand. Akuammicine N-Oxide is strongly formed h-bonds with crucial Mpro residues, Cys145, and His164.\r\n\r\nConclusion\r\nThe results provide lead that, the presence of Mpro\u2013 Akuammicine N-Oxide with highest Mpro binding energy along with other 34 chemical compounds having similar activity as part of AYUSH-64 make it a suitable candidate for repurposing to management of COVID-19 by further validating through experimental, clinical studies.","type":"Research","database":"PubMed","created":"2021-04-20"},{"id":601,"name":"SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study","author":"Krishnaprasad Baby, Swastika Maitya, Chetan H. Mehta, Akhil Suresh, Usha Y.Nayak, Yogendra Nayak","doi":"10.1016\/j.ejphar.2021.173922","abstract":"The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called \u201centry inhibitors.\u201d For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.","type":"Research","database":"PubMed","created":"2021-04-20"},{"id":600,"name":"Computational Estimation of Potential Inhibitors from the Known Drugs against the Main Protease of SARS-CoV-2","author":"Nguyen Minh Tam, Pham Minh Quan, Nguyen Xuan Ha, Pham Cam Nam, Huong Thi Thu Phung","doi":"10.26434\/chemrxiv.14102675.v1","abstract":"The coronavirus disease (COVID-19) pandemic caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to a global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempted to computationally screen for possible medications for COVID-19 via rapidly estimate the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twentyseven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.","type":"Research","database":"ChemRxiv","created":"2021-04-20"},{"id":599,"name":"Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses","author":"Nicola Borbone, Gennaro Piccialli, Giovanni Nicola Roviello, Giorgia Oliviero","doi":"10.3390\/molecules26040986","abstract":"Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.","type":"Review","database":"PubMed","created":"2021-04-12"},{"id":598,"name":"Brief review on repurposed drugs and vaccines for possible treatment of COVID-19","author":"Priyasha Dea, Ishita Chakraborty, Bhargavi Karnab, Nirmal Mazumder","doi":"10.1016\/j.ejphar.2021.173977","abstract":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic coronavirus disease 2019 (Covid-19) has claimed more than a million lives. Various in silico, in vitro, and in vivo studies are being conducted to understand the effect of SARS-CoV-2 on the cellular metabolism of humans and the various drugs and drug-targets that may be used. In this review, we discuss protein-protein interactions (PPIs) between viral and human proteins as well as viral targets like proteases. We try to understand the molecular mechanism of various repurposed antiviral drugs against SARS-CoV-2, their combination therapies, drug dosage regimens, and their adverse effects along with possible alternatives like non-toxic antiviral phytochemicals. Ultimately, randomized controlled trials are needed to identify which of these compounds has the required balance of efficacy and safety. We also focus on the recent advancements in diagnostic methods and vaccine candidates developed around the world to fight against Covid-19.","type":"Review","database":"PubMed","created":"2021-04-12"},{"id":596,"name":"Investigating the binding affinity, interaction, and structure-activity-relationship of 76 prescription antiviral drugs targeting RdRp and Mpro of SARS-CoV-2","author":"Sinthyia Ahmed, Rumana Mahtarin, Sayeda Samina Ahmed, Shaila Akter, Md. Shamiul Islam, Abdulla Al Mamun, Rajib Islam, Md Nayeem Hossain, Md Ackas Ali , Mossammad U. C. Sultana, MD. Rimon Parves, M. Obayed Ullah, Mohammad A. Halim","doi":"10.1080\/07391102.2020.1796804","abstract":"SARS-CoV-2 virus outbreak poses a major threat to humans worldwide due to its highly contagious nature. In this study, molecular docking, molecular dynamics, and structure-activity relationship are employed to assess the binding affinity and interaction of 76 prescription drugs against RNA dependent RNA polymerase (RdRp) and Main Protease (Mpro) of SARS-CoV-2. The RNA-dependent RNA polymerase is a vital enzyme of coronavirus replication\/transcription complex whereas the main protease acts on the proteolysis of replicase polyproteins. Among 76 prescription antiviral drugs, four drugs (Raltegravir, Simeprevir, Cobicistat, and Daclatasvir) that are previously used for human immunodeficiency virus (HIV), hepatitis C virus (HCV), Ebola, and Marburg virus show higher binding energy and strong interaction with active sites of the receptor proteins. To explore the dynamic nature of the interaction, 100\u2009ns molecular dynamics (MD) simulation is performed on the selected protein-drug complexes and apo-protein. Binding free energy of the selected drugs is performed by MM\/PBSA. Besides docking and dynamics, partial least square (PLS) regression method is applied for the quantitative structure activity relationship to generate and predict the binding energy for drugs. PLS regression satisfactorily predicts the binding energy of the effective antiviral drugs compared to binding energy achieved from molecular docking with a precision of 85%. This study highly recommends researchers to screen these potential drugs in vitro and in vivo against SARS-CoV-2 for further validation of utility.","type":"Research","database":"PubMed","created":"2021-04-12"},{"id":595,"name":"The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro","author":"Robert Konrat, Henrietta Papp, Val\u00e9ria Szij\u00e1rt\u00f3, Tanja Gesell, G\u00e1bor Nagy, M\u00f3nika Madai, Safia Zeghbib, Anett Kuczmog, Zs\u00f3fia Lanszki, Zsuzsanna Helyes, G\u00e1bor Kemenesi, Ferenc Jakab, Eszter Nagy","doi":"10.1101\/2020.09.15.296228","abstract":"Background: The COVID-19 pandemic is an enormous threat for healthcare systems and economies worldwide that urgently demands effective preventive and therapeutic strategies. Unlike the development of vaccines and new drugs specifically targeting SARS-CoV-2, repurposing of approved or clinically tested drugs can provide an immediate solution.\r\n\r\nMethods: We applied a novel computational approach to search among approved and clinically tested drugs from the DrugBank database. Candidates were selected based on Shannon entropy homology and predefined activity profiles of three small molecules with proven anti-SARS-CoV activity and a published data set. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 monkey kidney epithelial cells and reconstituted human nasal tissue. The effect on viral replication was assessed by quantification of viral genomes by droplet digital PCR.\r\n\r\nFindings: The computational approach with four independent queries identified major drug families, most often and in overlapping fashion anti-infective, anti-inflammatory, anti-hypertensive, anti-histamine and neuroactive drugs. Azelastine, an histamine 1 receptor-blocker, was predicted in multiple screens, and based on its attractive safety profile and availability in nasal formulation, was selected for experimental testing. Azelastine significantly reduced cytopathic effect and SARS-CoV-2 infection of Vero E6 cells with an EC50 of \u223c6 \u03bcM both in a preventive and treatment setting. Furthermore, azelastine in a commercially available nasal spray tested at 5-fold dilution was highly potent in inhibiting viral propagation in SARS-CoV-2 infected reconstituted human nasal tissue.\r\n\r\nInterpretations: Azelastine, an anti-histamine, available in nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization with SARS-CoV-2. As such, it could be useful in reducing viral spread and prophylaxis of COVID-19. Ultimately, its potential benefit should be proven in clinical studies.","type":"Research","database":"BioRxiv","created":"2021-04-11"},{"id":594,"name":"Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction","author":"ChangDong Lin, Yue Li, MengYa Yuan, MengWen Huang, Cui Liu, Hui Du, XingChao Pan, YaTing Wen, Xinyi Xu, Chenqi Xu, JianFeng Chen","doi":"10.1101\/2020.09.14.295956","abstract":"Coronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD\u2013ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 \u03bcM, which is far below the blood concentration (over 300 \u03bcM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.","type":"Research","database":"BioRxiv","created":"2021-04-11"},{"id":593,"name":"Allosteric Regulation of SARS-CoV-2 Protease: Towards Informed Structure-Based Drug Discovery","author":"Khaled Abdel-Maksoud, Mohamed Ali al-Badri, Christian Lorenz, Jonathan W. Essex","doi":"10.26434\/chemrxiv.12967655.v2","abstract":"The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic, definitive therapeutic agents for the treatment of the disease are yet to be identified. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2 MPro inhibitor design have generally neglected an allosteric mechanism linked to His41-Cys145 catalytic dyad disruption and thus fail to target the open conformational state. We identify the rare event associated with the allosteric regulation of MPro activity in the orientation of the His41 imidazole side chain away from Cys145. In this work, we show that molecular dynamics and metadynamics simulations are fundamental for performing computer-aided MPro inhibitor design where the sampling of this allosteric mechanism within a computationally feasible timescale is essential. We calculate a 4.2 \u00b1 1.9 kJ\/mol free energy difference between the open and closed states of the SARS-CoV-2 MPro active site, indicating that favourable ligand interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state.","type":"Research","database":"ChemRxiv","created":"2021-04-11"},{"id":592,"name":"In Silico Structure-Based Repositioning of Approved Drugs for Spike Glycoprotein S2 Domain Fusion Peptide of SARS-CoV-2: Rationale from Molecular Dynamics and Binding Free Energy Calculations","author":"Nishant Shekhar, Phulen Sarma, Manisha Prajapat, Pramod Avti, Hardeep Kaur, Anupam Raja, Harvinder Singh, Anusuya Bhattacharya, Saurabh Sharma, Subodh Kumar, Ajay Prakash, Bikash Medhi","doi":"10.1128\/mSystems.00382-20","abstract":"The membrane-anchored spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pivotal role in directing the fusion of the virus particle mediated by the host cell receptor angiotensin-converting enzyme 2 (ACE-2). The fusion peptide region of the S protein S2 domain provides SARS-CoV-2 with the biological machinery needed for direct fusion to the host lipid membrane. In our present study, computer-aided drug design strategies were used for the identification of FDA-approved small molecules using the optimal structure of the S2 domain, which exhibits optimal interaction ratios, structural features, and energy variables, which were evaluated based on their performances in molecular docking, molecular dynamics simulations, molecular mechanics\/generalized Born model and solvent accessibility binding free energy calculations of molecular dynamics trajectories, and statistical inferences. Among the 2,625 FDA-approved small molecules, chloramphenicol succinate, imipenem, and imidurea turned out to be the molecules that bound the best at the fusion peptide hydrophobic pocket. The principal interactions of the selected molecules suggest that the potential binding site at the fusion peptide region is centralized amid the Lys790, Thr791, Lys795, Asp808, and Gln872 residues.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":591,"name":"Repurposing drugs for treatment of SARS-CoV-2 infection: computational design insights into mechanisms of action","author":"Shubhangi Kandwal, Darren Fayne ","doi":"10.1080\/07391102.2020.1825232","abstract":"The COVID-19 pandemic has negatively affected human life globally. It has led to economic crises and health emergencies across the world, spreading rapidly among the human population and has caused many deaths. Currently, there are no treatments available for COVID-19 so there is an urgent need to develop therapeutic interventions that could be used against the novel coronavirus infection. In this research, we used computational drug design technologies to repurpose existing drugs as inhibitors of SARS-CoV-2 viral proteins. The Broad Institute\u2019s Drug Repurposing Hub consists of in-development\/approved drugs and was computationally screened to identify potential hits which could inhibit protein targets encoded by the SARS-CoV-2 genome. By virtually screening the Broad collection, using rationally designed pharmacophore features, we identified molecules which may be repurposed against viral nucleocapsid and non-structural proteins. The pharmacophore features were generated after careful visualisation of the interactions between co-crystalised ligands and the protein binding site. The ChEMBL database was used to determine the compound\u2019s level of inhibition of SARS-CoV-2 and correlate the predicted viral protein target with whole virus in vitro data. The results from this study may help to accelerate drug development against COVID-19 and the hit compounds should be progressed through further in vitro and in vivo studies on SARS-CoV-2.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":590,"name":"Integrative transcriptomics analysis of lung epithelial cells and identification of repurposable drug candidates for COVID-19","author":"Tania Islam, Md Rezanur Rahmana, Busra Aydin, Hande Beklen, Kazim Yalcin Arga, Md Shahjamand","doi":"10.1016\/j.ejphar.2020.173594","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has emerged as a world health pandemic. There are couples of treatment methods for COVID-19, however, well-established drugs and vaccines are urgently needed to treat the COVID-19. The new drug discovery is a tremendous challenge; repurposing of existing drugs could shorten the time and expense compared with de novo drug development. In this study, we aimed to decode molecular signatures and pathways of the host cells in response to SARS-CoV-2 and the rapid identification of repurposable drugs using bioinformatics and network biology strategies. We have analyzed available transcriptomic RNA-seq COVID-19 data to identify differentially expressed genes (DEGs). We detected 177 DEGs specific for COVID-19 where 122 were upregulated and 55 were downregulated compared to control (FDR<0.05 and logFC \u2265 1). The DEGs were significantly involved in the immune and inflammatory response. The pathway analysis revealed the DEGs were found in influenza A, measles, cytokine signaling in the immune system, interleukin-4, interleukin \u221213, interleukin \u221217 signaling, and TNF signaling pathways. Protein-protein interaction analysis showed 10 hub genes (BIRC3, ICAM1, IRAK2, MAP3K8, S100A8, SOCS3, STAT5A, TNF, TNFAIP3, TNIP1). The regulatory network analysis showed significant transcription factors (TFs) that target DEGs, namely FOXC1, GATA2, YY1, FOXL1, NFKB1. Finally, drug repositioning analysis was performed with these 10 hub genes and showed that in silico validated three drugs with molecular docking. The transcriptomics signatures, molecular pathways, and regulatory biomolecules shed light on candidate biomarkers and drug targets which have potential roles to manage COVID-19. ICAM1 and TNFAIP3 were the key hubs that have demonstrated good binding affinities with repurposed drug candidates. Dabrafenib, radicicol, and AT-7519 were the top-scored repurposed drugs that showed efficient docking results when they tested with hub genes. The identified drugs should be further evaluated in molecular level wet-lab experiments in prior to clinical studies in the treatment of COVID-19.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":589,"name":"In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm","author":"Laura Artigas, Mireia Coma , Pedro Matos-Filipe, Joaquim Aguirre-Plans, Judith Farr\u00e9s, Raquel Valls, Narcis Fernandez-Fuentes, Juan de la Haba-Rodriguez, Alex Olvera, Jose Barbera, Rafael Morales, Baldo Oliva, Jose Manuel Mas","doi":"10.1371\/journal.pone.0240149","abstract":"From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches. The drug combination of pirfenidone and melatonin has been identified as a candidate treatment that may contribute to reduce the virus infection. Starting from different drug targets the effect of the drugs converges on human proteins with a known role in SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server has been used as an alternative method to corroborate the effect of pirfenidone and melatonin against the infection of SARS-CoV-2. We have also predicted a potential therapeutic effect of the drug combination over the respiratory associated pathology, thus tackling at the same time two important issues in COVID-19. These evidences, together with the fact that from a medical point of view both drugs are considered safe and can be combined with the current standard of care treatments for COVID-19 makes this combination very attractive for treating patients at stage II, non-severe symptomatic patients with the presence of virus and those patients who are at risk of developing severe pulmonary complications.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":588,"name":"Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters","author":"Shuofeng Yuan, Runming Wang, Jasper Fuk-Woo Chan, Anna Jinxia Zhang, Tianfan Cheng, Kenn Ka-Heng Chik, Zi-Wei Ye, Suyu Wang, Andrew Chak-Yiu Lee, Lijian Jin, Hongyan Li, Dong-Yan Jin, Kwok-Yung Yuen, Hongzhe Sun ","doi":"10.1038\/s41564-020-00802-x","abstract":"SARS-CoV-2 is causing a pandemic of COVID-19, with high infectivity and significant mortality1. Currently, therapeutic options for COVID-19 are limited. Historically, metal compounds have found use as antimicrobial agents, but their antiviral activities have rarely been explored. Here, we test a set of metallodrugs and related compounds, and identify ranitidine bismuth citrate, a commonly used drug for the treatment of Helicobacter pylori infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo. Ranitidine bismuth citrate exhibited low cytotoxicity and protected SARS-CoV-2-infected cells with a high selectivity index of 975. Importantly, ranitidine bismuth citrate suppressed SARS-CoV-2 replication, leading to decreased viral loads in both upper and lower respiratory tracts, and relieved virus-associated pneumonia in a golden Syrian hamster model. In vitro studies showed that ranitidine bismuth citrate and its related compounds exhibited inhibition towards both the ATPase (IC50\u2009=\u20090.69\u2009\u00b5M) and DNA-unwinding (IC50\u2009=\u20090.70\u2009\u00b5M) activities of the SARS-CoV-2 helicase via an irreversible displacement of zinc(II) ions from the enzyme by bismuth(III) ions. Our findings highlight viral helicase as a druggable target and the clinical potential of bismuth(III) drugs or other metallodrugs for the treatment of SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":587,"name":"In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2","author":"Andr\u00e9s Pizzorno, Blandine Padey, Julia Dubois, Thomas Julien, Aur\u00e9lien Traversier, Victoria Duli\u00e8re, Pauline Bruna, Bruno Lina, Manuel Rosa-Calatrava, Olivier Terriera","doi":"10.1016\/j.antiviral.2020.104878","abstract":"In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 \u03bcM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir\/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.","type":"Other","database":"PubMed","created":"2021-04-11"},{"id":586,"name":"Computational investigation on Andrographis paniculata phytochemicals to evaluate their potency against SARS-CoV-2 in comparison to known antiviral compounds in drug trials","author":"Natarajan Arul Murugan, Chitra Jeyaraj Pandian, Jeyaraman Jeyakanthan","doi":"10.1080\/07391102.2020.1777901","abstract":"The outbreak due to SARS-CoV-2 (or Covid-19) is spreading alarmingly and number of deaths due to infection is aggressively increasing every day. Due to the rapid human to human transmission of Covid-19, we are in need to find a potent drug at the earliest by ruling-out the traditional time-consuming approach of drug development. This is only possible if we use reliable computational approaches for screening compounds from chemical space or by drug repurposing or by finding the phytochemicals and nutraceuticals from plants as they can be immediately used without the need for carrying out drug-trials to test safety and efficacy. A number of plant products were routinely suggested as drugs in traditional Indian and Chinese medicine. Here using molecular docking approach, and combined molecular dynamics and MM-GBSA based free energy calculations approach, we study the potency of the four selected phytochemicals namely andrographolide (AGP1), 14-deoxy 11,12-didehydro andrographolide (AGP2), neoandrographolide (AGP3) and 14-deoxy andrographolide (AGP4) from A. paniculata plant against the four key targets including three non-structural proteins (3\u2009L main protease (3CLpro), Papain-like proteinase (PLpro) and RNA-directed RNA polymerase (RdRp)) and a structural protein (spike protein (S)) of the virus which are responsible for replication, transcription and host cell recognition. The therapeutic potential of the selected phytochemicals against Covid-19 were also evaluated in comparison with a few commercially available drugs. The binding free energy data suggest that AGP3 could be used as a cost-effective drug-analog for treating covid-19 infection in developing countries.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":585,"name":"Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets","author":"Isabella Romeo, Francesco Mesiti, Antonio Lupia, Stefano Alcaro","doi":"10.3390\/molecules26030632","abstract":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified in China as the etiologic agent of the recent COVID-19 pandemic outbreak. Due to its high transmissibility, this virus quickly spread throughout the world, causing considerable health issues. The scientific community exerted noteworthy efforts to obtain therapeutic solutions for COVID-19, and new scientific networks were constituted. No certified drugs to efficiently inhibit the virus were identified, and the development of de-novo medicines requires approximately ten years of research. Therefore, the repurposing of natural products could be an effective strategy to handle SARS-CoV-2 infection. This review aims to update on current status of the natural occurring compounds recognizing SARS-CoV-2 druggable targets. Among the clinical trials actually recruited, some natural compounds are ongoing to examine their potential role to prevent and to treat the COVID-19 infection. Many natural scaffolds, including alkaloids, terpenes, flavonoids, and benzoquinones, were investigated by in-silico, in-vitro, and in-vivo approaches. Despite the large data set obtained by a computational approach, experimental evidences in most cases are not available. To fill this gap, further efforts to validate these results are required. We believe that an accurate investigation of naturally occurring compounds may provide insights for the potential treatment of COVID-19 patients.","type":"Review","database":"PubMed","created":"2021-04-11"},{"id":584,"name":"The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery","author":"Ziyang Fu, Bin Huang, Jinle Tang, Shuyan Liu, Ming Liu, Yuxin Ye, Zhihong Liu, Yuxian Xiong, Wenning Zhu, Dan Cao, Jihui Li, Xiaogang Niu, Huan Zhou, Yong Juan Zhao, Guoliang Zhang, Hao Huang ","doi":"10.1038\/s41467-020-20718-8","abstract":"SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1\u2009\u03bcM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":583,"name":"Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2","author":"Ziyad Tariq Muhseen, Alaa R. Hameed, Halah M. H. Al-Hasani, Sajjad Ahmad, Guanglin Li","doi":"10.3390\/molecules26030674","abstract":"SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, \u22128.7 kcal\/mol), PLpro (binding energy, \u22127.9 kcal\/mol), and Nucleocapsid (binding energy, \u22127.9 kcal\/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 \u00c5), PLpro (mean RMSD, 0.96 \u00c5), and Nucleocapsid (mean RMSD, 3.48 \u00c5)). Moreover, binding free energy analyses such as MMGB\/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, \u221224.42 kcal\/mol and MMPBSA, \u221210.80 kcal\/mol), PLpro (MMGBSA, \u221248.69 kcal\/mol and MMPBSA, \u221238.17 kcal\/mol) and Nucleocapsid (MMGBSA, \u221230.05 kcal\/mol and MMPBSA, \u221225.95 kcal\/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, \u221222.44 kcal\/mol), PLpro (mean, \u221225.46 kcal\/mol), and Nucleocapsid (mean, \u221223.30 kcal\/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2021-04-11"},{"id":582,"name":"Potential drug targets of SARS-CoV-2: From genomics to therapeutics","author":"Anas Shamsi, Taj Mohammad, Saleha Anwara, Samreen Amani, Mohd Shahnawaz Khan, Fohad Mabood Husaind, Md. Tabish Rehmane, Asimul Islama,Md Imtaiyaz Hassana","doi":"10.1016\/j.ijbiomac.2021.02.071","abstract":"The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from China has become a global threat due to the continuous rise in cases of Coronavirus disease 2019 (COVID-19). The problem with COVID-19 therapeutics is due to complexity of the mechanism of the pathogenesis of this virus. In this review, an extensive analysis of genome architecture and mode of pathogenesis of SARS-CoV-2 with an emphasis on therapeutic approaches is performed. SARS-CoV-2 genome consists of a single, ~29.9 kb long RNA having significant sequence similarity to BAT-CoV, SARS-CoV and MERS-CoV genome. Two-third part of SARS-Cov-2 genome comprises of ORF (ORF1ab) resulting in the formation of 2 polyproteins, pp1a and pp1ab, later processed into 16 smaller non-structural proteins (NSPs). The four major structural proteins of SARS-CoV-2 are the spike surface glycoprotein (S), a small envelope (E), membrane (M), and nucleocapsid (N) proteins. S protein helps in receptor binding and membrane fusion and hence plays the most important role in the transmission of CoVs. Priming of S protein is done by serine 2 transmembrane protease and thus plays a key role in virus and host cell fusion. This review highlights the possible mechanism of action of SARS-CoV-2 to search for possible therapeutic options.","type":"Review","database":"PubMed","created":"2021-04-11"},{"id":581,"name":"Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID-19","author":"Shikha Patel, Bhagawati Saxena, Priti Mehta","doi":"10.1016\/j.heliyon.2021.e06158","abstract":"Clinical studies have identified a cytokine storm in the third stage of disease progression in critical ill patients with coronavirus disease 2019 (COVID-19). Hence, effectively suppressing the uncontrolled immune response of the host towards the invaded viruses in a cytokine storm is a critical step to prevent the deterioration of patient conditions and decrease the rate of mortality. Therapeutic monoclonal antibodies (mAbs) are found to be effective for the management of acute respiratory distress syndrome in patients with COVID-19. In this review, we compiled all therapeutic mAbs targeting cytokine storm, which are in clinical trials for its repurposing in the management of COVID-19. Compilation of clinical trial data indicated that therapeutic monoclonal antibodies targeting interleukins (IL-6, IL-1ra, IL-8, IL-1\u03b2, IL-17A, IL-33), interferon-gamma, tumor necrosis factor-alpha, P-selectin, connective tissue growth factor, plasma kallikrein, tumor necrosis factor superfamily 14, granulocyte macrophage colony stimulating factor, colony stimulating factor 1 receptor, C\u2013C chemokine receptor type 5, cluster of differentiation 14 and 147, vascular endothelial growth factor, programmed cell death protein-1, Angiopoietin - 2, human factor XIIa, complementary protein 5, natural killer cell receptor G2A, human epidermal growth factor receptor 2, immunoglobulin-like transcript 7 receptor, complement component fragment 5a receptor and viral attachment to the human cell were under investigation for management of severely ill patients with COVID-19. Among these, about 65 clinical trials are targeting IL-6 inhibition as the most promising one and Tocilizumab, an IL-6 inhibitor is considered to be the potential candidate to treat cytokine storm associated with the COVID-19.","type":"Review","database":"PMC","created":"2021-04-11"},{"id":580,"name":"Mechanistic insight into anti-COVID-19 drugs: recent trends and advancements","author":"Hardeep Singh Tuli, Shivani Sood, Jagjit Kaur, Pawan Kumar, Prachi Seth, Sandeep Punia, Priya Yadav, Anil Kumar Sharma, Diwakar Aggarwal, Katrin Sak ","doi":"10.1007\/s13205-021-02644-8","abstract":"The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has been established now to be a deadly disease afflicting the whole world with worst consequences on healthcare, economy and day-to-day life activities. Being a communicable disease, which is highly pathogenic in humans, causing cough, throat infection, breathing problems, high fever, muscle pain, and may lead to death in some cases especially those having other comorbid conditions such as heart or kidney problems, and diabetes. Finding an appropriate drug and vaccine candidate against coronavirus disease (COVID-19) remains an ultimate and immediate goal for the global scientific community. Based on previous studies in the literature on SARS-CoV infection, there are a number of drugs that may inhibit the replication of SARS-CoV-2 and its infection. Such drugs comprise of inhibitors of Angiotensin-Converting Enzyme 2 (ACE2), transmembrane Serine Protease 2 (TMPRSS2), nonstructural protein 3C-like protease, nonstructural RNA-dependent RNA polymerase (RdRp) and many more. The antiviral drugs such as chloroquine and hydroxychloroquine, lopinavir and ritonavir as inhibitors for HIV protease, nucleotide analogue remdesivir, and broad-spectrum antiviral drugs are available to treat the SARS-CoV-2-infected patients. Therefore, this review article is planned to gain insight into the mechanism for blocking the entry of SARS-CoV-2, its validation, other inhibition mechanisms, and development of therapeutic drugs and vaccines against SARS-CoV-2.","type":"Review","database":"PMC","created":"2021-04-11"},{"id":579,"name":"Perspectives on Repurposed Drugs Based on Globally Accepted Therapeutic Guidelines to Combat SARS-CoV-2 Infection","author":"Rina Rosalia","doi":"10.2147\/DHPS.S272411","abstract":"A beta coronavirus was identified in Wuhan, China, in December 2019 and was named severe acute respiratory syndrome coronavirus-2. It spread globally at a rapid rate and killed innumerable people. The SARS-CoV-2 infection, also called coronavirus disease 2019, was declared a pandemic by WHO on March 11, 2020. The increasing number of SARS-CoV-2 related deaths is due to a number of reasons. A few antiviral, antimicrobial, and immune-based drugs have been repurposed for treatment as well as improvement of patient prognosis. These drugs are currently being studied in clinical trials conducted by the World Health Organization (WHO), National Institutes of Health (NIH), and other global health organizations to identify the agents that produce maximum positive patient outcomes and reduction in mortality rate. The aim of this article is to discuss the safety and efficacy of the repurposed drugs in SARS-CoV-2 infection based on currently available clinical evidence and to emphasize the importance of caution required whilst employing the international therapeutic guidelines. Also highlighted in this article are certain specific comorbid conditions, that either involve treatment with the repurposed drugs or have a direct impact of the virus in patients owing to their vulnerability.","type":"Review","database":"PMC","created":"2021-04-11"},{"id":578,"name":"AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19","author":"Steven S. Good, Jonna Westover, Kie Hoon Jung, Xiao-Jian Zhou, Adel Moussa, Paolo La Colla, Gabriella Collu, Bruno Canard, Jean-Pierre Sommadossi","doi":"10.1128\/AAC.02479-20","abstract":"The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47\u2009\u03bcM, very similar to its EC90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100\u2009\u03bcM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10\u2009\u03bcM AT-511 (698\u2009\u00b1\u200915 and 236\u2009\u00b1\u200914\u2009\u03bcM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550\u2009mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.","type":"Research","database":"PubMed","created":"2021-04-06"},{"id":577,"name":"Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug","author":"Camilla Isgr\u00f2, Anna Maria Sardanelli, Luigi Leonardo Palese","doi":"10.3390\/v13010106","abstract":"In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.","type":"Research","database":"PubMed","created":"2021-04-06"},{"id":576,"name":"Screening of FDA Approved Drugs Against SARS-CoV-2 Main Protease: Coronavirus Disease","author":"Vijayakumar Balakrishnan, Karthik Lakshminarayanan ","doi":"10.1007\/s10989-020-10115-6","abstract":"At the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission was human-to-human contact and hence resulted in a rapid surge across the globe where more than 24 million people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy, and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger\u2019s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir, and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.","type":"Research","database":"PMC","created":"2021-04-06"},{"id":575,"name":"Montelukast Drug May Improve COVID-19 Prognosis: A Review of Evidence","author":"Jean Barr\u00e9, Jean-Marc Sabatier, C\u00e9dric Annweiler","doi":"10.3389\/fphar.2020.01344","abstract":"With the lack of effective therapy, chemoprevention and vaccination, focusing on the immediate repurposing of existing drugs gives hope of curbing the pandemic. Interestingly, montelukast, a drug usually used in asthma, may be proposed as a potential adjuvant therapy in COVID-19. The aim of the present article was to review the properties of montelukast that could be beneficial in COVID-19. Ten experimentally supported properties were retrieved, either related to SARS-CoV-2 (antiviral properties, prevention of endotheliitis and of neurological disorders linked to SARS-CoV-2), and\/or related to the host (improvement of atherogenic vascular inflammation, limitation of the ischemia\/reperfusion phenomenon, improvement of respiratory symptoms), and\/or related to serious COVID-19 outcomes (limitation of the cytokine storm, mitigation of acute respiratory distress syndrome), and\/or related to tissue sequelae (antioxidant properties, anti-fibrosis effects). Based on gathered theoretical evidence, we argue that montelukast should be further tested to prevent and treat COVID-19 outcomes.","type":"Review","database":"PMC","created":"2021-04-06"},{"id":574,"name":"Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)","author":"Sophie Juul ,Emil Eik Nielsen, Joshua Feinberg, Faiza Siddiqui, Caroline Kamp J\u00f8rgensen, Emily Barot, Niklas Nielsen, Peter Bentzer, Areti Angeliki Veroniki, Lehana Thabane, Fanlong Bu, Sarah Klingenberg, Christian Gluud, Janus Christian Jakobsen","doi":"10.1371\/journal.pmed.1003293","abstract":"Background\r\nCoronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed.\r\n\r\nMethods and findings\r\nThis is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology.\r\n\r\nWe included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75\u20130.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62\u20130.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40\u20131.37; p = 0.34, I2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80\u20131.11; p = 0.48, I2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63\u20130.94; p = 0.009, I2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial.\r\n\r\nMeta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97\u20131.19; p = 0.17; I2 = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96\u20131.18; p = 0.21; I2 = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01\u20132.87; p < 0.00001; I2 = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir\u2013ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39\u20131.04; p = 0.07, I2 = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85\u20131.53; p = 0.38, I2 = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33\u20131.10; p = 0.10, I2 = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects.\r\n\r\nNone of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors.\r\n\r\nConclusions\r\nOur results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.","type":"Review","database":"PMC","created":"2021-04-06"},{"id":573,"name":"A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease","author":"Jeremy D. Baker, Rikki L. Uhrich, Gerald C. Kraemer, Jason E. Love, Brian C. Kraemer","doi":"10.1101\/2020.07.10.197889","abstract":"The SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic 1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly. The overall case fatality rate for COVID-19 is estimated to be \u223c2.3% overall 3 and 32.3% in hospitalized patients age 70-79 years 4. Therapeutic options for treating the underlying viremia in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of \u223c6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found \u223c50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 \u2264 50 \u03bcM. Hits from our screen are enriched with hepatitis C NS3\/4A protease targeting drugs including Boceprevir (IC50=0.95 \u03bcM), Ciluprevir (20.77\u03bcM). Narlaprevir (IC50=1.10\u03bcM), and Telaprevir (15.25\u03bcM). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3\/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.","type":"Research","database":"BioRxiv","created":"2021-03-29"},{"id":572,"name":"Targeting SARS-COV-2 non-structural protein 16: a virtual drug repurposing study","author":"Elham Tazikeh-Lemeski, Sajad Moradi, Rahim Raoufi, Mohsen Shahlaei, Mehr Ali Mahmood Janlou, Samaneh Zolghadri","doi":"10.1080\/07391102.2020.1779133","abstract":"Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been performed by a virtual drug repurposing approach. First, drug shape-based screening (among FDA approved drugs) with a known template of MTase inhibitor, sinefungin was done and best compounds with high similarity scores were selected. In addition to the selected compounds, 4 nucleoside analogs of anti-viral (Raltgravir, Maraviroc and Favipiravir) and anti-inflammatory (Prednisolone) drugs were selected for further investigations. Then, binding energies and interaction modes were found by molecular docking approaches and compouds with lower energy were selected for further investigation. After that, Molecular dynamics (MD) simulation was carried to test the potential selected compounds in a realistic environment. The results showed that Raltegravir and Maraviroc among other compounds can bind strongly to the active site of the protein compared to sinefungin, and can be potential candidates to inhibit NSP-16. Also, the MD simulation results suggested that the Maraviroc and Raltegravir are more effective drug candidates than Sinefungin for inhibiting the enzyme. It is concluded that Raltegravir and Maraviroc which may be used in the treatment of COVID-19 after Invitro and invivo studies and clinical trial for final confirmation of drug effectiveness.","type":"Research","database":"PubMed","created":"2021-03-29"},{"id":571,"name":"In-silico drug repurposing for targeting SARS-CoV-2 main protease (Mpro)","author":"Shilpa Sharma, Shashank Deep ","doi":"10.1080\/07391102.2020.1844058","abstract":"COVID-19, caused by novel coronavirus or SARS-CoV-2, is a viral disease which has infected millions worldwide. Considering the urgent need of the drug for fighting against this infectious disease, we have performed in-silico drug repurposing followed by molecular dynamics (MD) simulation and MM-GBSA calculation. The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses, therefore, this was screened for already known FDA approved drugs and some natural compounds. Comparison of docking and MD simulation results of complexes of drugs with that of inhibitor N3 (experimentally obtained) suggests EGCG, withaferin, dolutegravir, artesunate as potential inhibitors of the main protease (Mpro). Further, in silico docking and MD simulation suggest that EGCG analogues ZINC21992196 and ZINC 169337541 may act as a better inhibitor.","type":"Research","database":"PubMed","created":"2021-03-29"},{"id":569,"name":"Familiar dermatologic drugs as therapies for COVID-19","author":"M.Ortega-Pe\u00f1a, R.Gonz\u00e1lez-Cuevas","doi":"10.1016\/j.adengl.2020.09.015","abstract":"Researchers the world over are working to find the treatments needed to reduce the negative effects of coronavirus disease 2019 (COVID-19) and improve the current prognosis of patients. Several drugs that are often used in dermatology are among the potentially useful treatments: ivermectin, antiandrogenic agents, melatonin, and the antimalarial drugs chloroquine and hydroxychloroquine. These and other agents, some of which have proven controversial, are being scrutinized by the scientific community. We briefly review the aforementioned dermatologic drugs and describe the most recent findings relevant to their use against COVID-19.","type":"Review","database":"PMC","created":"2021-03-23"},{"id":568,"name":"Dual inhibition of SARS-CoV-2 spike and main protease through a repurposed drug, rutin","author":"Anchala Kumari, Vikrant Singh Rajput, Priya Nagpal, Himanshi Kukrety, Sonam Grover, Abhinav Grover","doi":"10.1080\/07391102.2020.1864476","abstract":"The global health emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to alarming numbers of fatalities across the world. So far the researchers worldwide have not been able to discover a breakthrough in the form of a potent drug or an effective vaccine. Therefore, it is imperative to discover drugs to curb the ongoing menace. In silico approaches using FDA approved drugs can expedite the drug discovery process by providing leads that can be pursued. In this report, two drug targets, namely the spike protein and main protease, belonging to structural and non-structural class of proteins respectively, were utilized to carry out drug repurposing based screening. The exposed nature of the spike protein on the viral surface along with its instrumental role in host infection and the involvement of main protease in processing of polyproteins along with no human homologue make these proteins attractive drug targets. Interestingly, the screening identified a common high efficiency binding molecule named rutin. Further, molecular dynamics simulations in explicit solvent affirmed the stable and sturdy binding of rutin with these proteins. The decreased Rg value (4\u2009nm for spike-rutin and 2.23\u2009nm for main protease-rutin) and stagnant SASA analysis (485\u2009nm\/S2\/N in spike-rutin and 152\u2009nm\/S2\/N in main protease-rutin) for protein surface and its orientation in the exposed and buried regions suggests a strong binding interaction of the drug. Further, cluster analysis and secondary structure analysis of complex trajectories validated the conformational changes due to binding of rutin.","type":"Research","database":"PMC","created":"2021-03-23"},{"id":567,"name":"The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials","author":"Kimberley Lewis, Dipayan Chaudhuri, Fayez Alshamsi, Laiya Carayannopoulos, Karin Dearness, Zain Chagla, Waleed Alhazzani","doi":"10.1371\/journal.pone.0244778","abstract":"Background\r\nPopulations such as healthcare workers (HCW) that are unable to practice physical distancing are at high risk of acquiring Coronavirus disease-2019 (COVID-19). In these cases pharmacological prophylaxis would be a solution to reduce severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) transmission. Hydroxychloroquine has in vitro antiviral properties against SARS CoV-2. We therefore sought to determine the efficacy and safety of hydroxychloroquine as prophylaxis for COVID-19.\r\n\r\nMethods and findings\r\nWe electronically searched EMBASE, MEDLINE, the Cochrane COVID-19 Register of Controlled Trials, Epistemonikos COVID-19, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform up to September 28th, 2020 for randomized controlled trials (RCTs). We calculated pooled relative risks (RRs) for dichotomous outcomes with the corresponding 95% confidence intervals (CIs) using a random-effect model. We identified four RCTs (n = 4921) that met our eligibility criteria. The use of hydroxychloroquine, compared to placebo, did not reduce the risks of developing COVID-19 (RR 0.82, 95% CI 0.65 to 1.04, moderate certainty), hospitalization (RR 0.72, 95% CI 0.34 to 1.50, moderate certainty), or mortality (RR 3.26, 95% CI 0.13 to 79.74, low certainty), however, hydroxychloroquine use increased the risk of adverse events (RR 2.76, 95% CI 1.38 to 5.55, moderate certainty).\r\n\r\nConclusion\r\nAlthough pharmacologic prophylaxis is an attractive preventive strategy against COVID-19, the current body of evidence failed to show clinical benefit for prophylactic hydroxychloroquine and showed a higher risk of adverse events when compared to placebo or no prophylaxis.","type":"Review","database":"PMC","created":"2021-03-23"},{"id":566,"name":"In Silico Drug Repositioning Against Human NRP1 to Block SARS-CoV-2 Host Entry","author":"Seref Gul","doi":"10.3906\/biy-2012-52","abstract":"Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here I took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARS-CoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM\/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr297, Trp301, and Tyr353 amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19.","type":"Research","database":"ChemRxiv","created":"2021-03-17"},{"id":564,"name":"Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2","author":"Althaf Shaik, Nalini Natarajan, Sivapriya Kirubakaran, Vijay Thiruvenkatam","doi":"10.26434\/chemrxiv.13265519.v1","abstract":"This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act\r\nagainst Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have\r\nconsidered maximum resources available on Nsp15 including the recent crystal structure solution of the\r\nprotein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an\r\nimportant target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work\r\nis our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening\r\n(HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics\r\nsimulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet\r\ncritical attempt by undertaking this work; we hope that our work once published may be of help in carrying out\r\nappropriate wet-lab work. We declare that this manuscript is original, has not been published before and is not\r\ncurrently being considered for publication elsewhere.\"\r\n","type":"Research","database":"ChemRxiv","created":"2021-03-08"},{"id":563,"name":"A Study of Potential SARS-CoV-2 Antiviral Drugs and Preliminary Research of Their Molecular Mechanism, Based on Anti-SARS-CoV Drug Screening and Molecular Dynamics Simulation","author":"Xiaomeng Zhao, Ruixia Liu, Zhi Miao, Nan Ye, Wenyu Lu","doi":"10.1089\/cmb.2020.0112","abstract":"This research was based on virtual docking screening and molecular dynamics simulation among the 30 drugs analyzed, which drug had the best inhibitory effect on 3CL protease (Mpro) hydrolase. AutoDock Vina is used for molecular docking. Through our research, the binding affinity of saquinavir and raltegravir to the protein is higher than other candidate drugs in molecular docking; they are \u22129.1 kcal\/mol and \u22129 kcal\/mol, respectively. Among them remdesivir performance was mediocre, only \u22127.9 kcal\/mol. In our study, ultimately, these systems are also basically stable. The overall contraction of the protein structure is most obvious after the combination of remdesivir. In the remdesivir-protein system, the structure of the terminal end has undergone relatively large changes. And the total number of hydrogen bonds formed in the remdesivir-protein system is larger. The hydrogen bonds can be maintained for a longer time, and the final interaction energy is stronger than other systems. These amino acid sequence fragments have high affinity with the remdesivir molecule. Remdesivir can change the structure of the protein to make it stronger in binding with itself through the interaction with the protein. The simulation study of drug screening for new coronaviruses can provide further support for new coronavirus effective drugs and provide powerful support to defeat the virus.","type":"Research","database":"PubMed","created":"2021-03-08"},{"id":562,"name":"Repurposing Anti-Cancer Drugs for COVID-19 Treatment","author":"Nicholas Borcherding, Yogesh Jethava, Praveen Vikas","doi":"10.2147\/DDDT.S282252","abstract":"The novel coronavirus disease 2019 (COVID-19) pandemic has caused catastrophic damage to human life across the globe along with social and financial hardships. According to the Johns Hopkins University Coronavirus Resource Center, more than 41.3 million people worldwide have been infected, and more than 1,133,000 people have died as of October 22, 2020. At present, there is no available vaccine and a scarcity of efficacious therapies. However, there is tremendous ongoing effort towards identifying effective drugs and developing novel vaccines. Early data from Adaptive COVID-19 Treatment Trials (ACTT) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and compassionate use study have shown promise for remdesivir, leading to emergency authorization by the Food and Drug Administration (FDA) for treatment of hospitalized COVID-19 patients. However, several randomized studies have now shown no benefit or increased adverse events associated with remdesivir treatment. Drug development is a time-intensive process and requires extensive safety and efficacy evaluations. In contrast, drug repurposing is a time-saving and cost-effective drug discovery strategy geared towards using existing drugs instead of de novo drug discovery. Treatments for cancer and COVID-19 often have similar goals of controlling inflammation, inhibiting cell division, and modulating the host microenvironment to control the disease. In this review, we focus on anti-cancer drugs that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials.","type":"Review","database":"PMC","created":"2021-03-08"},{"id":561,"name":"Computational drug repurposing study of the RNA binding domain of SARS\u2010CoV\u20102 nucleocapsid protein with antiviral agents","author":"Gizem Tatar, Ezgi Ozyurt, Kemal Turhan","doi":"10.1002\/btpr.3110","abstract":"The recent outbreak of coronavirus disease (COVID\u201019) in China caused by the severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) has led to worldwide human infections and deaths. The nucleocapsid (N) protein of coronaviruses (CoVs) is a multifunctional RNA binding protein necessary for viral RNA replication and transcription. Therefore, it is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. This study addresses the potential to repurpose antiviral compounds approved or in development for treating human CoV induced infections against SARS\u2010CoV\u20102 N. For this purpose, we used the docking methodology to better understand the inhibitory mechanism of this protein with the existing 34 antiviral compounds. The results of this analysis indicate that rapamycin, saracatinib, camostat, trametinib, and nafamostat were the top hit compounds with binding energy (\u221211.87, \u221210.40, \u22129.85, \u22129.45, \u22129.35\u2009kcal\/mol, respectively). This analysis also showed that the most common residues that interact with the compounds are Phe66, Arg68, Gly69, Tyr123, Ile131, Trp132, Val133, and Ala134. Subsequently, protein\u2010ligand complex stability was examined with molecular dynamics simulations for these five compounds, which showed the best binding affinity. According to the results of this study, the interaction between these compounds and crucial residues of the target protein were maintained. These results suggest that these residues are potential drug targeting sites for the SARS\u2010CoV\u20102 N protein. This study information will contribute to the development of novel compounds for further in vitro and in vivo studies of SARS\u2010CoV\u20102, as well as possible new drug repurposing strategies to treat COVID\u201019 disease.","type":"Research","database":"PubMed","created":"2021-03-08"},{"id":560,"name":"Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection","author":"Brian C. Procter, Casey Ross, Vanessa Pickard, Erica Smith, Cortney Hanson, Peter A. McCullough","doi":"10.31083\/j.rcm.2020.04.260","abstract":"There is an emergency need for early ambulatory treatment of Coronavirus Disease 2019 (COVID-19) in acutely ill patients in an attempt to reduce disease progression and the risks of hospitalization and death. Such management should be applied in high-risk patients age > 50 years or with one or more medical problems including cardiovascular disease. We evaluated a total of 922 outpatients from March to September 2020. All patients underwent contemporary real-time polymerase chain reaction (PCR) assay tests from anterior nasal swab samples. Patients age 50.5 \u00b1 13.7 years (range 12 to 89), 61.6% women, at moderate or high risk for COVID-19 received empiric management via telemedicine. At least two agents with antiviral activity against SARS-CoV-2 (zinc, hydroxychloroquine, ivermectin) and one antibiotic (azithromycin, doxycycline, ceftriaxone) were used along with inhaled budesonide and\/or intramuscular dexamethasone consistent with the emergent science on early COVID-19 treatment. For patients with high severity of symptoms, urgent in-clinic administration of albuterol nebulizer, inhaled budesonide, and intravenous volume expansion with supplemental parenteral thiamine 500 mg, magnesium sulfate 4 grams, folic acid 1 gram, vitamin B12 1 mg. A total of 320\/922 (34.7%) were treated resulting in 6\/320 (1.9%) and 1\/320 (0.3%) patients that were hospitalized and died, respectively. We conclude that early ambulatory (not hospitalized, treated at home), multidrug therapy is safe, feasible, and associated with low rates of hospitalization and death. Early treatment should be considered for high-risk patients as an emergency measure while we await randomized trials and guidelines for ambulatory management.","type":"Review","database":"PubMed","created":"2021-03-08"},{"id":559,"name":"QSAR Modeling of SARS\u2010CoV Mpro Inhibitors Identifies Sufugolix, Cenicriviroc, Proglumetacin, and other Drugs as Candidates for Repurposing against SARS\u2010CoV\u20102","author":"Vinicius M. Alves, Tesia Bobrowski, Cleber C. Melo\u2010Filho, Daniel Korn, Scott Auerbach, Charles Schmitt, Eugene N. Muratov, Alexander Tropsha","doi":"10.1002\/minf.202000113","abstract":"The main protease (Mpro) of the SARS\u2010CoV\u20102 has been proposed as one of the major drug targets for COVID\u201019. We have identified the experimental data on the inhibitory activity of compounds tested against the closely related (96\u2009% sequence identity, 100\u2009% active site conservation) Mpro of SARS\u2010CoV. We developed QSAR models of these inhibitors and employed these models for virtual screening of all drugs in the DrugBank database. Similarity searching and molecular docking were explored in parallel, but docking failed to correctly discriminate between experimentally active and inactive compounds, so it was not relied upon for prospective virtual screening. Forty\u2010two compounds were identified by our models as consensus computational hits. Subsequent to our computational studies, NCATS reported the results of experimental screening of their drug collection in SARS\u2010CoV\u20102 cytopathic effect assay (https:\/\/opendata.ncats.nih.gov\/covid19\/). Coincidentally, NCATS tested 11 of our 42\u2005hits, and three of them, cenicriviroc (AC50 of 8.9\u2005\u03bcM), proglumetacin (tested twice independently, with AC50 of 8.9\u2005\u03bcM and 12.5\u2005\u03bcM), and sufugolix (AC50 12.6\u2005\u03bcM), were shown to be active. These observations support the value of our modeling approaches and models for guiding the experimental investigations of putative anti\u2010COVID\u201019 drug candidates. All data and models used in this study are publicly available via Supplementary Materials, GitHub (https:\/\/github.com\/alvesvm\/sars\u2010cov\u2010mpro), and Chembench web portal (https:\/\/chembench.mml.unc.edu\/).","type":"Research","database":"PubMed","created":"2021-03-08"},{"id":558,"name":"The Current Status of Drug Repositioning and Vaccine Developments for the COVID-19 Pandemic","author":"Jung-Hyun Won, Howard Lee","doi":"10.3390\/ijms21249775","abstract":"Since the outbreak of coronavirus disease 2019 (COVID-19) was first identified, the world has vehemently worked to develop treatments and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented speed. Few of the repositioned drugs for COVID-19 have shown that they were efficacious and safe. In contrast, a couple of vaccines against SARS-CoV-2 will be ready for mass rollout early next year. Despite successful vaccine development for COVID-19, the world will face a whole new set of challenges including scale-up manufacturing, cold-chain logistics, long-term safety, and low vaccine acceptance. We highlighted the importance of knowledge sharing and collaboration to find innovative answers to these challenges and to prepare for newly emerging viruses.","type":"Review","database":"PubMed","created":"2021-03-08"},{"id":557,"name":"Drug Repurposing Approach against Novel Coronavirus Disease (COVID-19) through Virtual Screening Targeting SARS-CoV-2 Main Protease","author":"Kamrul Hasan Chowdhury, Md. Riad Chowdhury, Shafi Mahmud, Abu Montakim Tareq, Nujhat Binte Hanif, Naureen Banu, A. S. M. Ali Reza, Talha Bin Emran, Jesus Simal-Gandara","doi":"10.3390\/biology10010002","abstract":"Novel coronavirus disease (COVID-19) was identified from China in December 2019 and spread rapidly through human-to-human transmission, affecting so many people worldwide. Until now, there has been no specific treatment against the disease and repurposing of the drug. Our investigation aimed to screen potential inhibitors against coronavirus for the repurposing of drugs. Our study analyzed sequence comparison among SARS-CoV, SARS-CoV-2, and MERS-CoV to determine the identity matrix using discovery studio. SARS-CoV-2 Mpro was targeted to generate an E-pharmacophore hypothesis to screen drugs from the DrugBank database having similar features. Promising drugs were used for docking-based virtual screening at several precisions. Best hits from virtual screening were subjected to MM\/GBSA analysis to evaluate binding free energy, followed by the analysis of binding interactions. Furthermore, the molecular dynamics simulation approaches were carried out to assess the docked complex\u2019s conformational stability. A total of 33 drug classes were found from virtual screening based on their docking scores. Among them, seven potential drugs with several anticancer, antibiotic, and immunometabolic categories were screened and showed promising MM\/GBSA scores. During interaction analysis, these drugs exhibited different types of hydrogen and hydrophobic interactions with amino acid residue. Besides, 17 experimental drugs selected from virtual screening might be crucial for drug discovery against COVID-19. The RMSD, RMSF, SASA, Rg, and MM\/PBSA descriptors from molecular dynamics simulation confirmed the complex\u2019s firm nature. Seven promising drugs for repurposing against SARS-CoV-2 main protease (Mpro), namely sapanisertib, ornidazole, napabucasin, lenalidomide, daniquidone, indoximod, and salicylamide, could be vital for the treatment of COVID-19. However, extensive in vivo and in vitro studies are required to evaluate the mentioned drug\u2019s activity.","type":"Research","database":"PubMed","created":"2021-03-08"},{"id":556,"name":"Liquiritin from Glycirrhyza Glabra L (Fabaceae) - a Natural Derived Drug, as a Potential Inhibitor for SARS-CoV-2","author":"Akash Vanzara, Ravi Patel, Amisha Patel, Nimisha Patel, Kapil Yadav, Padamnabhi Nagar","doi":"10.26434\/chemrxiv.13853345.v1","abstract":"Novel Corona virus-2 (Covid-19) is spreading and causing major damage around the globe and constantly increasing daily. There is a prerequisite of expeditious development of safe and efficient drugs for such a contagious disease. In this regard, utilization of a computational approach with an aim to provide potential enzyme inhibitors derived from natural resources will give a providential therapy. The present study investigated one of the promising plants namely Glycyrrhiza glabra L. It has various medicinal properties viz. anti-inflammatory, anti-cancer, anti-demulcent, expectorant, etc. In-Silico Analysis of liquiritin against SARS-CoV-2 Mpro was carried out using Autodock 4.2.6 and results were compared with presently prescribed drugs i.e. dexamethasone, remdesivir, hydroxychloroquine, and azithromycin. The binding energy of liquiritin was found to be -6.62 kcal\/mol. It shows presence of hydrogen bond, hydrophobic interaction and electrostatic interaction with six active residues THR26, GLY143, CYS145, HIS 164, GLU166, and GLN189. Comparative studies investigated that dexamethasone, remdesivir, hydroxychloroquine, and azithromycin have four (THR26, GLY143, CYS145, GLU166), three (CYS145, GLU166, GLN189), four (GLY143, CYS145, HIS 164, GLN189) and two (GLU166, GLN189) identical active residues, respectively. The present study recommended liquiritin as a potential candidate against SARS-CoV-2 as it is naturally derived and has tremendous traditional usage against various diseases. However, in-vitro and in-vivo studies are required to prove its efficacy.","type":"Research","database":"ChemRxiv","created":"2021-03-08"},{"id":555,"name":"Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors","author":" Wei-Chung Chiou, Meng-Shiuan Hsu, Yun-Ti Chen, Jinn-Moon Yang, Yeou-Guang Tsay, Hsiu-Chen Huang, Cheng Huang","doi":"10.1080\/14756366.2020.1850710","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Since its emergence, the COVID-19 pandemic has not only distressed medical services but also caused economic upheavals, marking urgent the need for effective therapeutics. The experience of combating SARS-CoV and MERS-CoV has shown that inhibiting the 3-chymotrypsin-like protease (3CLpro) blocks the replication of the virus. Given the well-studied properties of FDA-approved drugs, identification of SARS-CoV-2 3CLpro inhibitors in an FDA-approved drug library would be of great therapeutic value. Here, we screened a library consisting of 774 FDA-approved drugs for potent SARS-CoV-2 3CLpro inhibitors, using an intramolecularly quenched fluorescence (IQF) peptide substrate. Ethacrynic acid, naproxen, allopurinol, butenafine hydrochloride, raloxifene hydrochloride, tranylcypromine hydrochloride, and saquinavir mesylate have been found to block the proteolytic activity of SARS-CoV-2 3CLpro. The inhibitory activity of these repurposing drugs against SARS-CoV-2 3CLpro highlights their therapeutic potential for treating COVID-19 and other Betacoronavirus infections.","type":"Research","database":"PubMed","created":"2021-03-03"},{"id":554,"name":"Enfuvirtide, an HIV-1 fusion inhibitor peptide, can act as a potent SARS-CoV-2 fusion inhibitor: an in silico drug repurposing study","author":"Khadijeh Ahmadi, Alireza Farasat, Mosayeb Rostamian, Behrooz Johari, Hamid Madanchi","doi":"10.1080\/07391102.2021.1871958","abstract":"Regarding the urgency of therapeutic measures for coronavirus disease 2019 (COVID-19) pandemic, the use of available drugs with FDA approval is preferred because of the less time and cost required for their development. In silico drug repurposing is an accurate way to speed up the screening of the existing FDA-approved drugs to find a therapeutic option for COVID-19. The similarity in SARS-CoV-2 and HIV-1 fusion mechanism to host cells can be a key point for Inhibit SARS-CoV-2 entry into host cells by HIV fusion inhibitors. Accordingly, in this study, an HIV-1 fusion inhibitor called Enfuvirtide (Enf) was selected. The affinity and essential residues involving in the Enf binding to the S2 protein of SARS-CoV-2, HIV-1 gp41 protein and angiotensin-converting enzyme 2 (ACE-2) as a negative control, was evaluated using molecular docking. Eventually, Enf-S2 and Enf-gp41 protein complexes were simulated by molecular dynamics (MD) in terms of binding affinity and stability. Based on the most important criteria such as docking score, cluster size, energy and dissociation constant, the strongest interaction was observed between Enf with the S2 protein. In addition, MD results confirmed that Enf-S2 protein interaction was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations. In conclusion, it can be stated that Enf can act as a strong SARS-CoV-2 fusion inhibitor and demonstrates the potential to enter the clinical trial phase of COVID-19.","type":"Research","database":"PubMed","created":"2021-03-03"},{"id":553,"name":"Effective drugs used to combat SARS-CoV-2 infection and the current status of vaccines","author":"Annoor Awadasseid, Yanling Wu, Yoshimasa Tanaka, Wen Zhang","doi":"10.1016\/j.biopha.2021.111330","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causal factor of the coronavirus disease 2019 (COVID-19). Drug repurposing, portraying patented drugs as a successful drug development technique, could shorten the period and minimize costs relative to de novo drug exploration. Recently several drugs have been used as anti-SARS-CoV-2 such as Remdesivir, Favipiravir, Hydroxychloroquine, Azithromycin, Lopinavir\/Ritonavir, Nafamostat mesylate and so on. Despite such efforts, there is currently no successful broad-spectrum antiviral countermeasures to combat SARS-CoV-2 or possibly potential CoVs pandemic. Therefore it is desperately important to recognize and test widely efficient, reliable anti-CoV therapies now and in the future. Remdesivir and Favipiravir were more promising despite having side effects; it had prominent efficacy and efficiency while still not yet approved as the official anti-viral drug for SARS CoV-2. In this review, we summarizes the current drug and vaccine discovery status against SARS-CoV-2, predicting that these efforts will help create effective drugs and vaccines for SARS-CoV-2.","type":"Review","database":"PubMed","created":"2021-03-03"},{"id":552,"name":"A review of potential suggested drugs for coronavirus disease (COVID-19) treatment","author":"Parastoo Tarighi, Samane Eftekhari, Milad Chizari, Mahsa Sabernavaei, Davod Jafari, Parastoo Mirzabeigi","doi":"10.1016\/j.ejphar.2021.173890","abstract":"The latest pandemic, coronavirus disease-2019 (COVID-19), is associated with high prevalence and easy transmission, which is expanding globally with no conventional treatment or vaccine. The new virus revealed 79% and 50% genomic similarities with severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), respectively. Accordingly, since the disease resists testing and adopting new therapeutics, repositioning pre-existing drugs may present a fast and attractive strategy with known safety, characteristics, and dosage used. However, they are not specific and targeted. Therefore, several drugs have been investigated for their efficacy and safety in the treatment of COVID-19; most of them are undergoing clinical trials. This article summarizes clinical investigations of potential therapeutic drugs used as COVID-19 therapy. Subsequently, it prepares a pattern of results and therapeutic targets to help further experiment designs. We have investigated drugs as classified in the following three groups; 1) The drugs which computationally showed effectiveness (in silico) but needed further lab confirmations; 2) Emetine, Teicoplanin, and Nelfinavir have shown effectiveness in vitro; 3) The drugs currently under clinical trial.","type":"Review","database":"PMC","created":"2021-03-03"},{"id":551,"name":"Repurposing Screens of FDA-Approved Drugs Identify 29 Inhibitors of SARS-CoV-2","author":"Keun Bon Ku, Hye Jin Shin, Hae Soo Kim, Bum-Tae Kim, Seong-Jun Kim, Chonsaeng Kim","doi":"10.4014\/jmb.2009.09009","abstract":"COVID-19, caused by the novel coronavirus SARS-CoV-2, has spread globally and caused serious social and economic problems. The WHO has declared this outbreak a pandemic. Currently, there are no approved vaccines or antiviral drugs that prevent SARS-CoV-2 infection. Drugs already approved for clinical use would be ideal candidates for rapid development as COVID-19 treatments. In this work, we screened 1,473 FDA-approved drugs to identify inhibitors of SARS-CoV-2 infection using cell-based assays. The antiviral activity of each compound was measured based on the immunofluorescent staining of infected cells using anti-dsRNA antibody. Twenty-nine drugs among those tested showed antiviral activity against SARS-CoV-2. We report this new list of inhibitors to quickly provide basic information for consideration in developing potential therapies.","type":"Research","database":"PubMed","created":"2021-02-23"},{"id":550,"name":"Drug Repurposing of Allophenylnorstatine Containing HIV-Protease Inhibitors Against SARS-CoV-2 Mpro: Insights from Molecular Dynamics Simulations and Binding Free Energy Estimations","author":"Jiban Jyoti Dash, Priyanka Purohit, Jules Tshishimbi Muya, Biswa Ranjan Meher","doi":"10.26434\/chemrxiv.12402545.v1","abstract":"Coronavirus-2 Main protease (SARS-CoV-2 Mpro), one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and a crucial target for drug discovery, has been battered with numerous types of drugs\/inhibitors. Regrettably, till date there is no any potential drugs or effective inhibitors available to combat its action. Based on the reports of HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 Mpro, we have chosen few clinically trialed experimental HIV-protease inhibitors (JE-2147, KNI-227 and KNI-272) and a variant JE2-CH3, to examine their binding affinities with SARS-CoV-2 Mpro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the rational elucidation of the binding mechanism of these four inhibitors to SARS-CoV-2 Mpro by merging molecular docking, Molecular Dynamics (MD) simulation, and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (-14.95 kcal\/mol) compared to JE2-CH3 (--11.19 kcal\/mol), KNI-227 (-13.93 kcal\/mol) and KNI-272 (-12.84 kcal\/mol) against SARS-CoV-2 Mpro. The increase in binding affinity for JE-2147 comparative to other three inhibitors arises due to an increased favorable van der Waals interactions and decreased solvation energies between the inhibitor and viral protease. Residue decomposition analysis and hydrogen bonding pattern confirms binding affinities of the inhibitors crucial for the interactions. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Pro168, Gln189 etc.) from the active site or near the active site regions with more than 1.0 kcal\/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 Mpro drugs.","type":"Research","database":"ChemRxiv","created":"2021-02-23"},{"id":549,"name":"Prevention of SARS-CoV-2 cell entry: insight from in silico interaction of drug-like alkaloids with spike glycoprotein, human ACE2, and TMPRSS2","author":"Gideon A. Gyebi , Adegbenro P. Adegunloye, Ibrahim M. Ibrahim, Oludare M. Ogunyemi, Saheed O. Afolabi, Olalekan B. Ogunro","doi":"10.1080\/07391102.2020.1835726","abstract":"COVID-19 is a respiratory disease caused by SARS-CoV-2, an enveloped positive sense RNA virus. The SARS-CoV-2 spike glycoprotein, human angiotensin-converting enzyme 2 (ACE2) and human transmembrane protease serine 2 (TMPRSS2) are essential for the host cell-mediated viral entry. Targeting these proteins represent viable options to stop the first stage of infection and transmission. Hence, 97 alkaloids from African medicinal plants with reported antiviral activity were evaluated for this purpose via in silico studies. These alkaloids were docked for their interactions with SARS-CoV-2 spike glycoprotein, ACE2, and TMPRSS2. Top 20 alkaloids with highest binding affinities were further screened for their interactions with spike glycoprotein of SARS-CoV and MERS-CoV, and with ACE2-SARS-CoV-2 receptor-binding domain complex (ACE2-RBD). The energy profiling, molecular dynamics simulation (MDS), binding free energy base on Molecular Mechanics\/Generalized Born Surface Area (MMGBSA), clustering of MDS trajectories, and virtual physicochemical and pharmacokinetic screening of the best docked alkaloids were performed. Results revealed that more than 15 alkaloids interacted better than the reference compounds. 10\u2013Hydroxyusambarensine and Cryptospirolepine were docked in a similar binding pattern to the S1-specificy pocket of TMPRSS2 as camostat (reference inhibitor). The strong binding affinities, stability of the alkaloid-protein complexes and amino acid interactions displayed by cryptospirolepine, 10-hydroxyusambarensine, and cryptoquindoline with important binding hotspots of the proteins suggest these alkaloids have the potential of altering the capacity of SARS-CoV-2 membrane mediated host cell entry. Further in vitro and in vivo evaluation of these \u201cdrug-like\u201d alkaloids as potential inhibitors of coronavirus cell entry is proposed.","type":"Research","database":"PubMed","created":"2021-02-23"},{"id":548,"name":"Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review","author":"Afif Nakhleh, Naim Shehadeh","doi":"10.1016\/j.dsx.2020.04.040","abstract":"Background\r\nDiabetes mellitus is associated with a more severe course of coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme II (ACE2) receptor for host cell entry. We aimed to assess the interactions between antihyperglycemic drugs and the renin-angiotensin system (RAS) and their putative roles in COVID-19.\r\n\r\nMethods\r\nA literature search was performed using Pubmed to review the interrelationships between hyperglycemia, RAS and COVID-19, and the effects of antihyperglycemic medications.\r\n\r\nResults\r\nThe RAS has an essential role in glucose homeostasis and may have a role in COVID-19-induced lung injury. Some antihyperglycemic medications modulate RAS and might hypothetically alleviate the deleterious effect of angiotensin II on lung injury. Furthermore, most antihyperglycemic medications showed anti-inflammatory effects in animal models of lung injury.\r\n\r\nConclusions\r\nSome antihyperglycemic medications might have protective effects against COVID-19-induced lung injury. Early insulin therapy seems very promising in alleviating lung injury.","type":"Review","database":"PMC","created":"2021-02-15"},{"id":547,"name":"Drug repurposing strategies for COVID-19","author":"Suranga L Senanayake","doi":"10.4155\/fdd-2020-0010","abstract":"COVID-19 has now been declared a pandemic and new treatments are urgently needed as we enter a phase beyond containment. Developing new drugs from scratch is a lengthy process, thus impractical to face the immediate global challenge. Drug repurposing is an emerging strategy where existing medicines, having already been tested safe in humans, are redeployed to combat difficult-to-treat diseases. While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, as was for HIV in the 1990s; the urgent question now being which combination.","type":"Comment","database":"PMC","created":"2021-02-15"},{"id":546,"name":"Drug Repurposing for COVID-19 from FDA Approved and Experiment Stage Drugs by in Silico Methods with SARS CoV-2 Spike Protein","author":"Sharanya CS, Arun Kumar, Abhithaj J, Sabu A, Haridas Madathilkovilakathu","doi":"10.26434\/chemrxiv.12324980.v1","abstract":"E-pharmacophore based virtual screening of DrugBank database is carried out to identify candidate drugs for repurposing. The dug molecules were screened based on the pharmacophore generated and filtered through the 6000 drug molecule to obtain better 2000 of them. This filtered drug molecules further screened via structure based approach, involving molecular docking at different precisions. From the large database seven drug lead molecules were selected as hits and their binding energy with the spike protein were calculated. Cladribine, Clofarabine, Fludarabine from approved category and 7-methyl-guanosine-5'-triphosphate-5'-guanosine, Adenosine-2'-5'-Diphosphate, 8-Bromo-Adenosine-5'-Monophosphate, Alpha-Methylene Adenosine Monophosphate in the experimental category were found to be potent inhibitors of SARS CoV-2 spike protein to repurpose as drugs for COVID-19.","type":"Research","database":"ChemRxiv","created":"2021-02-09"},{"id":545,"name":"Drug repurposing and cytokine management in response to COVID-19: A review","author":"Luana Heimfarth , Mairim Russo Serafinic, Paulo Ricardo Martins-Filho, Jullyana de Souza Siqueira Quintans, Lucindo Jos\u00e9 Quintans-J\u00fanior","doi":"10.1016\/j.intimp.2020.106947","abstract":"Coronavirus disease 2019 (COVID-19), the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an aggressive disease that attacks the respiratory tract and has a higher fatality rate than seasonal influenza. The COVID\u201019 pandemic is a global health crisis, and no specific therapy or drug has been formally recommended for use against SARS-CoV-2 infection. In this context, it is a rational strategy to investigate the repurposing of existing drugs to use in the treatment of COVID-19 patients. In the meantime, the medical community is trialing several therapies that target various antiviral and immunomodulating mechanisms to use against the infection. There is no doubt that antiviral and supportive treatments are important in the treatment of COVID-19 patients, but anti-inflammatory therapy also plays a pivotal role in the management COVID-19 patients due to its ability to prevent further injury and organ damage or failure. In this review, we identified drugs that could modulate cytokines levels and play a part in the management of COVID-19. Several drugs that possess an anti-inflammatory profile in others illnesses have been studied in respect of their potential utility in the treatment of the hyperinflammation induced by SAR-COV-2 infection. We highlight a number of antivirals, anti-rheumatic, anti-inflammatory, antineoplastic and antiparasitic drugs that have been found to mitigate cytokine production and consequently attenuate the \u201ccytokine storm\u201d induced by SARS-CoV-2. Reduced hyperinflammation can attenuate multiple organ failure, and even reduce the mortality associated with severe COVID-19. In this context, despite their current unproven clinical efficacy in relation to the current pandemic, the repurposing of drugs with anti-inflammatory activity to use in the treatment of COVID-19 has become a topic of great interest.","type":"Review","database":"PMC","created":"2021-02-03"},{"id":544,"name":"Immunosuppressive Drugs and COVID-19: A Review","author":"Tessa S. Schoot, Ang\u00e8le P. M. Kerckhoffs, Luuk B. Hilbrands, Rob J. van Marum","doi":"10.3389\/fphar.2020.01333","abstract":"Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently unknown whether immunosuppressive drugs are advantageous or detrimental in patients with COVID-19. Immunosuppressive drugs could be harmful in the initial phase of COVID-19. In this phase, the host immune response is necessary to inhibit viral replication. However, immunosuppressive drugs might have a beneficial effect in the later, more severe phase of COVID-19. In this phase, an overshoot of the host immune response (the \u201ccytokine storm\u201d) can cause ARDS, multiorgan failure and mortality.\r\n\r\nAim: To summarize the available evidence on the effect of immunosuppressive drugs on infection with SARS-CoV-2. The effects of immunosuppressive drugs on similar pandemic coronaviruses may resemble the effects on SARS-CoV-2. Thus, we also included studies on the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)\r\n\r\nMethods: The study protocol was registered in PROSPERO (registration number CRD42020181137). We included randomized controlled trials (RCTs), cohort studies with a control group and case-control studies concerning humans \u2265 18 years old. We also included in-vitro studies and animal studies with a control group.\r\n\r\nResults and Conclusion: Sixty-nine studies were included. Interestingly, MPA inhibits SARS-CoV-2 replication in-vitro. Clinical studies are needed to confirm the inhibitory effect of MPA on SARS-CoV-2 replication in-vivo. There are indications that corticosteroids and IL-6 inhibitors, like tocilizumab, can reduce mortality and prevent mechanical ventilation in patients with COVID-19. However, observational studies have contradictory results and the risk of bias is high. Thus, these results have to be confirmed in high-quality clinical trials before these drugs can be implemented as standard care. Based on the positive results of CNIs, mTOR inhibitors and thiopurine analogues in in-vitro studies with SARS-CoV and MERS-CoV, it would be interesting to investigate their effects on SARS-CoV-2 replication.","type":"Review","database":"PMC","created":"2021-02-03"},{"id":543,"name":"Brilacidin, a COVID-19 Drug Candidate, Exhibits Potent In Vitro Antiviral Activity Against SARS-CoV-2","author":"Allison Bakovic, Kenneth Risner, Nishank Bhalla, Farhang Alem, Theresa L. Chang, Warren Weston, Jane A. Harness, Aarthi Narayanan","doi":"10.1101\/2020.10.29.352450","abstract":"Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than one million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins\/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin\u2014a de novo designed synthetic small molecule that captures the biological properties of HDPs\u2014on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is primarily a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin has demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 and thus supports brilacidin as a promising COVID-19 drug candidate.","type":"Research","database":"BioRxiv","created":"2021-02-01"},{"id":542,"name":"High-throughput virtual screening of drug databanks for potential inhibitors of SARS-CoV-2 spike glycoprotein","author":"Ibrahim E. Awad, Abd Al-Aziz A. Abu-Saleh, Sweta Sharma, Arpita Yadav, Raymond A. Poirier","doi":"10.1080\/07391102.2020.1835721","abstract":"COVID-19, which is caused by a novel coronavirus known as SARS-CoV-2, has spread rapidly around the world, and it has infected more than 29 million individuals as recorded on 16 September 2020. Much effort has been made to stop the virus from spreading, and there are currently no approved pharmaceutical products to treat COVID-19. Here, we apply an in silico approach to investigate more than 3800 FDA approved drugs on the viral RBD S1-ACE2 interface as a target. The compounds were investigated through flexible ligand docking, ADME property calculations and protein\u2013ligand interaction maps. Molecular dynamics (MD) simulations were also performed on eleven compounds to study the stability and the interactions of the protein\u2013ligand complexes. The MD simulations show that bagrosin, chidamide, ebastine, indacaterol, regorafenib, salazosulfadimidine, silodosin and tasosartan are relatively stable near the C terminal domain (CTD1) of the S1 subunit of the viral S protein. The relative MMGBSA binding energies show that silodosin has the best binding to the target. The constant velocity steered molecular dynamics (SMD) simulations show that silodosin preferentially interacts with the RBD S1 and has potential to act as an interfering compound between viral spike\u2013host ACE2 interactions.","type":"Research","database":"PubMed","created":"2021-02-01"},{"id":541,"name":"Anti-malarial Drugs are Not Created Equal for SARS-CoV-2 Treatment: A Computational Analysis Evidence","author":"Simone Ronsisvalle, Federica Panarello, Rosaria Di Mauro, Renato Bernardini, Giovanni Li Volti, Giuseppina Cantarella","doi":"10.2174\/1381612826666201210092736","abstract":"Background: The evolution of the pandemic is putting national healthcare systems to a huge effort worldwide and at present, there is no preferred antiviral treatment for COVID-19. Recently, SARS-Cov-2 protease structure was released and may be exploited in in-silico studies in order to conduct molecular docking analysis.\r\n\r\nMethods: In particular, we compared the binding of two used antimalarial drugs (i.e. chloroquine and hydroxychloroquine) which showed some potential clinical effects in COVID-19 patients, using as positive control tree antiviral recognized compounds, ritonavir, lopinavir and darunavir.\r\n\r\nResults: Our results showed that hydroxychloroquine but not chloroquine exhibited a significant binding activity to the main protease similar to that possessed by protease inhibitors tested for other viral infections.\r\n\r\nConclusion: Our data suggest that hydroxychloroquine may exert additional direct antiviral activity compared to chloroquine. In the absence of clinical studies comparing the efficacy of these two compounds, hydroxychloroquine may offer additional effects and may be considered as first choice.","type":"Research","database":"PubMed","created":"2021-02-01"},{"id":540,"name":"Repurposing potential of FDA\u2010approved and investigational drugs for COVID\u201019 targeting SARS\u2010CoV\u20102 spike and main protease and validation by machine learning algorithm","author":"Akalesh Kumar Verma, Rohit Aggarwal","doi":"10.1111\/cbdd.13812","abstract":"The present study aimed to assess the repurposing potential of existing antiviral drug candidates (FDA\u2010approved and investigational) against SARS\u2010CoV\u20102 target proteins that facilitates viral entry and replication into the host body. To evaluate molecular affinities between antiviral drug candidates and SARS\u2010CoV\u20102 associated target proteins such as spike protein (S) and main protease (Mpro), a molecular interaction simulation was performed by docking software (MVD) and subsequently the applicability score was calculated by machine learning algorithm. Furthermore, the STITCH algorithm was used to predict the pharmacology network involving multiple pathways of active drug candidate(s). Pharmacophore features of active drug(s) molecule was also determined to predict structure\u2013activity relationship (SAR). The molecular interaction analysis showed that cordycepin has strong binding affinities with S protein (\u2212180) and Mpro proteins (\u2212205) which were relatively highest among other drug candidates used. Interestingly, compounds with low IC50 showed high binding energy. Furthermore, machine learning algorithm also revealed high applicability scores (0.42\u20130.47) of cordycepin. It is worth mentioning that the pharmacology network depicted the involvement of cordycepin in different pathways associated with bacterial and viral diseases including tuberculosis, hepatitis B, influenza A, viral myocarditis, and herpes simplex infection. The embedded pharmacophore features with cordycepin also suggested strong SAR. Cordycepin's anti\u2010SARS\u2010CoV\u20102 activity indicated 65% (E\u2010gene) and 42% (N\u2010gene) viral replication inhibition after 48h of treatment. Since, cordycepin has both preclinical and clinical evidences on antiviral activity, in addition the present findings further validate and suggest repurposing potential of cordycepin against COVID\u201019.","type":"Research","database":"PubMed","created":"2021-02-01"},{"id":539,"name":"Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection","author":"Ramesh K. Goyal, Jaseela Majeed, Rajiv Tonk, Mahaveer Dhobi, Bhoomika Patel, Kalicharan Sharma, Subbu Apparsundaram","doi":"10.31083\/j.rcm.2020.03.118","abstract":"Angiotensin-converting enzyme 2 (ACE2), the host cell-binding site for SAR-CoV-2, poses two-fold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNA-dependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19.","type":"Review","database":"PubMed","created":"2021-02-01"},{"id":538,"name":"Antiviral Drug Discovery To Address the COVID-19 Pandemic","author":"Douglas D. Richman","doi":"10.1128\/mBio.02134-20","abstract":"The magnitude of the morbidity and mortality inflicted upon the global population in less than 1 year has driven the inescapable conclusion that the discovery and development of effective antiviral drugs for COVID-19 are urgent and should be prioritized. The antiviral drug discovery programs that emerged for HIV and hepatitis C virus have enabled technology and expertise to accelerate this process for SARS-CoV-2. The description of candidate lead inhibitors for the viral main protease (Mpro) exemplifies this accelerated approach and reminds us of the needs and opportunities for addressing this pandemic.","type":"Comment","database":"PubMed","created":"2021-02-01"},{"id":536,"name":"COVID-19: Drug Targets and Potential Treatments","author":"Carmen Gil, Tiziana Ginex, In\u00e9s Maestro, Vanesa Nozal, Luc\u00eda Barrado-Gil, Miguel \u00c1ngel Cuesta-Geijo, Jes\u00fas Urquiza, David Ram\u00edrez, Covadonga Alonso, Nuria E. Campillo, and Ana Martinez","doi":"10.1021\/acs.jmedchem.0c00606","abstract":"Currently, humans are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which threatens public health worldwide. To date, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. In this paper, we will focus on the main virus-based and host-based targets that can guide efforts in medicinal chemistry to discover new drugs for this devastating disease. In principle, all CoV enzymes and proteins involved in viral replication and the control of host cellular machineries are potentially druggable targets in the search for therapeutic options for SARS-CoV-2. This Perspective provides an overview of the main targets from a structural point of view, together with reported therapeutic compounds with activity against SARS-CoV-2 and\/or other CoVs. Also, the role of innate immune response to coronavirus infection and the related therapeutic options will be presented.","type":"Review","database":"PubMed","created":"2021-02-01"},{"id":535,"name":"Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research","author":"SABRINA BIMONTE, ANNA CRISPO, ALFONSO AMORE, EGIDIO CELENTANO, ARTURO CUOMO, MARCO CASCELLA","doi":"10.21873\/invivo.11949","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir\/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.","type":"Review","database":"ChemRxiv","created":"2021-02-01"},{"id":534,"name":"Comprehensive review on the prevailing COVID-19 therapeutics and the potential of repurposing SARS-CoV-1 candidate drugs to target SARS-CoV-2 as a fast-track treatment and prevention option","author":"Shanthi Sabarimurugan, Arun Dharmarajan, Sudha Warrier, Maheswari Subramanian, Rajarajan Swaminathan","doi":"10.21037\/atm-20-4071","abstract":"The recent seemingly uncontrollable pandemic caused by the novel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has been able to spread quickly due to the non-availability of effective antivirals or vaccines. The virus has structural and non-structural proteins that are considered as possible targets. Receptor recognition is the critical determinant and preliminary phase of viral infection to enter the host cell and causes tissue tropism. We have conducted a comprehensive review of relevant publication on in vitro, in silico, in vivo and clinical evaluation of drug candidates ranging from broad-spectrum antivirals to natural molecules targeted towards viral spike protein in addition to evaluate their suitability as therapies based on an analysis of the similarities between SARS-CoV-1 and SARS-CoV-2. In general, antiviral targets are based on two strategies, either targeting the host or the host\u2019s immune cell. We have reviewed the available details on the SARS-CoV-2 strain\u2019s host-viral binding sites entry mechanism, alongside recently tested effective antivirals. The hypothesis of this review may provide clear insight for researchers and physicians who are struggling to narrow down scientific options to control the current pandemic. Overall, we found that the promising efficacious drug candidates reported against SARS-CoV-1 could be considered for drug repurposing; this might help to identify a potential drug for therapeutic measures and development of vaccine for COVID-19.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":533,"name":"Drug screening and development from the affinity of S protein of new coronavirus with ACE2","author":"Yue-Peng Jiang, Xiao-Xuan Zhao, Hui-Qing Lv, Cheng-Ping Wen","doi":"10.1007\/s10096-020-04048-7","abstract":"Recently, various studies have shown that angiotensin-converting enzyme 2 (ACE2) acts as the \u201cdoorknob\u201d that can be bound by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which conduces to its entrance to the host cells, and plays an important role in corona virus disease 2019 (COVID-19). This paper aims to collect and sorts out the existing drugs, which exert the ability to block the binding of S protein and ACE2 so as to provide directions for the later drug development. By reviewing the existing literature, we expound the pathogenesis of SARS-CoV-2 from the perspective of S protein and ACE2 binding, and summarize the drugs and compounds that can interfere with the interaction of spike protein and ACE2 receptor from different ways. We summarized five kinds of substances, including peptide P6, griffithsin, hr2p analogs, EK1, vaccine, monoclonal antibody, cholesterol-depleting agents, and extracts from traditional Chinese medicine. They can fight SARS-CoV-2 by specifically binding to ACE2 receptor, S protein, or blocking membrane fusion between the host and virus. ACE2 is the key point for SARS-CoV-2 to enter the cells, and it is also the focus of drug intervention. Our drug summary on this pathomechanism is expected to provide ideas for the drug research on SARS-CoV-2 and help to develop anti-coronavirus drugs of broad spectrum for future epidemics.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":532,"name":"Potential Repurposing of Drugs with Anti-SARS-CoV-2 Activity in Preclinical Trials: A Systematic Review","author":"Yasmim Mendes Rocha, Gabriel Ac\u00e1cio de Moura, Juliana Ramos de Oliveira, Larissa Deadame de Figueiredo Nicolete, Roberto Nicolete","doi":"10.2174\/0929867327666201005113204","abstract":"COVID-19 is an emerging outbreak similar to previous pandemics caused by Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Till date, SARS-CoV-2 infection is still spreading, representing a major threat to public health, where several control measures are being practiced in order to culminate its spread. The research and development of new drugs require a lot of funding in addition to being a slow and costly process. As a result, new techniques have been proposed to streamline this process. The repositioning or repurposing of drugs represents an attractive strategy, presenting a promising way to introduce new drugs. Currently, numerous reused drugs are already available in the market and are in practice. In this review, it was observed that the antiviral drugs Entricitabine and Tenofovir display potential therapeutic efficacy in preclinical studies. Therefore, in silico analyses were considered a potential tool for predicting the effectiveness of drugs, mainly as an effective approach to encourage a complementary in vitro and in vivo antiviral evaluation.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":531,"name":"Novel insights into the treatment of SARS-CoV-2 infection: An overview of current clinical trials","author":"Fatemeh Oroojalian, Ali Haghbin, Behzad Baradaran, Nima Hemmat, Mohammad-Ali Shahbazi, Hossein Bannazadeh Baghi, Ahad Mokhtarzadeh, Michael R.Hamblin","doi":"10.1016\/j.ijbiomac.2020.09.204","abstract":"The emergence of the global pandemic caused by the novel SARS-CoV-2 virus has motivated scientists to find a definitive treatment or a vaccine against it in the shortest possible time. Current efforts towards this goal remain fruitless without a full understanding of the behavior of the virus and its adaptor proteins. This review provides an overview of the biological properties, functional mechanisms, and molecular components of SARS-CoV-2, along with investigational therapeutic and preventive approaches for this virus. Since the proteolytic cleavage of the S protein is critical for virus penetration into cells, a set of drugs, such as chloroquine, hydroxychloroquine, camostat mesylate have been tested in clinical trials to suppress this event. In addition to angiotensin-converting enzyme 2, the role of CD147 in the viral entrance has also been proposed. Mepolizumab has shown to be effective in blocking the virus's cellular entrance. Antiviral drugs, such as remdesivir, ritonavir, oseltamivir, darunavir, lopinavir, zanamivir, peramivir, and oseltamivir, have also been tested as treatments for COVID-19. Regarding preventive vaccines, the whole virus, vectors, nucleic acids, and structural subunits have been suggested for vaccine development. Mesenchymal stem cells and natural killer cells could also be used against SARS-CoV-2. All the above-mentioned strategies, as well as the role of nanomedicine for the diagnosis and treatment of SARS-CoV-2 infection, have been discussed in this review.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":530,"name":"Severe acute respiratory syndrome\u2010coronavirus\u20102: Current advances in therapeutic targets and drug development","author":"Sakthivel Suganya, Suresh Divya, Madasamy Parani","doi":"10.1002\/rmv.2174","abstract":"The current pandemic of severe acute respiratory syndrome\u2010coronavirus\u20102 (SARS\u2010CoV\u20102) has quickly emerged as a global health concern with government bodies worldwide taking drastic control measures. Understanding the virology of SARS\u2010CoV\u20102, its molecular mechanisms, and its pathogenesis are required for a targeted therapeutic approach. In this review, we highlight the current molecular and drug advances that target SARS\u2010CoV\u20102 at the genome level. We also summarize studies that therapeutically target the host angiotensin\u2010converting enzyme 2 and proteases. Finally, we summarize antibody\u2010mediated therapeutic approaches, as well as recent trends in vaccine development. Hence, the purpose of this study is to investigate different molecular targets in SARS\u2010CoV\u20102 pathogenesis and their usefulness in developing strategies for drug development.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":529,"name":"Repositioning of Drugs to Counter COVID-19 Pandemic - An Insight","author":"Sai M. Akilesh, Rajesh J, Dhanabal Palanisamy, Ashish Wadhwani","doi":"10.2174\/1389201021999200820155927","abstract":"COVID-19 is a coronavirus pandemic, caused by the novel coronavirus 2 (SARS-CoV-2) severe acute respiratory syndrome. The devastating impact of this novel coronavirus outbreak has necessitated the need for rapid and effective anti-viral therapies against SARS-CoV-2, to contain the spread of disease and importantly, alleviate the severe life-threatening symptoms and disorders. Drug repurposing strategy offers an attractive, immediate and realistic approach to tackle this growing pandemic of COVID-19. Due to the similarities with SARS-CoV-1 virus and phylogenetic relation to MERS-CoV virus, accelerated screening of approved drugs and development of repositioning strategies have proved to be critical in the survival of many COVID-19 patients. Numerous scientific investigations from the initial years of coronavirus outbreak along with upcoming advances of immunotherapy and vaccines may prove to be beneficial. Currently, several repurposing strategies are under different phases of clinical trials and provide with definitive framework for the development of future therapies for the effective treatment of COVID-19. This review article summarizes the latest developments and trends in drug repurposing strategy for COVID-19 treatment.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":528,"name":"Covid-19: Pathophysiology; Mechanism of Transmission and Possible Molecular Drug Target for Management","author":"Asis Bala, Abhijit Sengupta, Motlalepula Gilbert Matsabisa, Hlupheka P Chabalala","doi":"10.2174\/1874467213999200831104324","abstract":"Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronaviruses 2 (SARS-CoV-2). At present it is potentially a fatal disease and is of great global public health concern. The pathophysiological understanding of the mode of transmission of COVID-9 and the possible molecular targets are exploring successively to fight against this contagious disease. In this pandemic situation large number of countries have been forced to do social distancing and lockdown. The two main pathways of SARS-CoV-2 transmission include (1) droplet infection via the respiratory secretions or by close person to person contact whereas (2) faecal to oral route transmission is also possible. Thus, the route of entry of SARS-CoV-2 are through the nasal and or oral cavity. Here we reviewed briefly the current knowledge about COVID-19, considering the potential explanation of the mode of transmission and the different possible molecular drug targets. We highlighted potential approaches to address the antiviral therapy inhibiting the replication of SARS-CoV-2 in the host targeting (a.) RNA-dependent RNA polymerase (b.) serine protease and (c.) proteolytic activation pathways or the cell membrane receptor called the angiotensin converting enzyme-2 (ACE2). The recently exercised immuno-enhancement therapy to fight against SARS-CoV-2 and treatment strategy using drug combination are also explored here in this review.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":527,"name":"Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses","author":"Anna Arteseab, Valentina Svicherc, Giosu\u00e8 Costa, Romina Salpini, Velia Chiara Di Maio, Mohammad Alkhatib, Francesca Alessandra Ambrosio, Maria Mercedes Santoroc, Yehuda G. Assaraf, Stefano Alcaro, Francesca Ceccherini-Silberstein","doi":"10.1016\/j.drup.2020.100721","abstract":"Coronaviridae is a peculiar viral family, with a very large RNA genome and characteristic appearance, endowed with remarkable tendency to transfer from animals to humans. Since the beginning of the 21st century, three highly transmissible and pathogenic coronaviruses have crossed the species barrier and caused deadly pneumonia, inflicting severe outbreaks and causing human health emergencies of inconceivable magnitude. Indeed, in the past two decades, two human coronaviruses emerged causing serious respiratory illness: severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV), causing more than 10,000 cumulative cases, with mortality rates of 10 % for SARS-CoV-1 and 34.4 % for MERS-CoV. More recently, the severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) has emerged in China and has been identified as the etiological agent of the recent COVID-19 pandemic outbreak. It has rapidly spread throughout the world, causing nearly 22 million cases and \u223c 770,000 deaths worldwide, with an estimated mortality rate of \u223c3.6 %, hence posing serious challenges for adequate and effective prevention and treatment. Currently, with the exception of the nucleotide analogue prodrug remdesivir, and despite several efforts, there is no known specific, proven, pharmacological treatment capable of efficiently and rapidly inducing viral containment and clearance of SARS-CoV-2 infection as well as no broad-spectrum drug for other human pathogenic coronaviruses. Another confounding factor is the paucity of molecular information regarding the tendency of coronaviruses to acquire drug resistance, a gap that should be filled in order to optimize the efficacy of antiviral drugs.\r\n\r\nIn this light, the present review provides a systematic update on the current knowledge of the marked global efforts towards the development of antiviral strategies aimed at coping with the infection sustained by SARS-CoV-2 and other human pathogenic coronaviruses, displaying drug resistance profiles. The attention has been focused on antiviral drugs mainly targeting viral protease, RNA polymerase and spike glycoprotein, that have been tested in vitro and\/or in clinical trials as well as on promising compounds proven to be active against coronaviruses by an in silico drug repurposing approach. In this respect, novel insights on compounds, identified by structure-based virtual screening on the DrugBank database endowed by multi-targeting profile, are also reported. We specifically identified 14 promising compounds characterized by a good in silico binding affinity towards, at least, two of the four studied targets (viral and host proteins). Among which, ceftolozane and NADH showed the best multi-targeting profile, thus potentially reducing the emergence of resistant virus strains. We also focused on potentially novel pharmacological targets for the development of compounds with anti-pan coronavirus activity. Through the analysis of a large set of viral genomic sequences, the current review provides a comprehensive and specific map of conserved regions across human coronavirus proteins which are essential for virus replication and thus with no or very limited tendency to mutate. Hence, these represent key druggable targets for novel compounds against this virus family. In this respect, the identification of highly effective and innovative pharmacological strategies is of paramount importance for the treatment and\/or prophylaxis of the current pandemic but potentially also for future and unavoidable outbreaks of human pathogenic coronaviruses.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":526,"name":"Emerging strategies on in silico drug development against COVID-19: challenges and opportunities","author":"Manisha Yadav, Swasti Dhagat, J. Satya Eswari","doi":"10.1016\/j.ejps.2020.105522","abstract":"The importance of coronaviruses as human pathogen has been highlighted by the recent outbreak of SARS-CoV-2 leading to the search of suitable drugs to overcome respiratory infections caused by the virus. Due to the lack of specific drugs against coronavirus, the existing antiviral and antimalarial drugs are currently being administered to the patients infected with SARS-CoV-2. The scientists are also considering repurposing of some of the existing drugs as a suitable option in search of effective drugs against coronavirus till the establishment of a potent drug and\/or vaccine. Computer-aided drug discovery provides a promising attempt to enable scientists to develop new and target specific drugs to combat any disease. The discovery of novel targets for COVID-19 using computer-aided drug discovery tools requires knowledge of the structure of coronavirus and various target proteins present in the virus. Targeting viral proteins will make the drug specific against the virus, thereby, increasing the chances of viral mortality. Hence, this review provides the structure of SARS-CoV-2 virus along with the important viral components involved in causing infection. It also focuses on the role of various target proteins in disease, the mechanism by which currently administered drugs act against the virus and the repurposing of few drugs. The gap arising from the absence of specific drugs is addressed by proposing potential antiviral drug targets which might provide insights into structure-based drug development against SARS-CoV-2.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":525,"name":"Based on Principles and Insights of COVID-19 Epidemiology, Genome Sequencing, and Pathogenesis: Retrospective Analysis of Sinigrin and ProlixinRX (Fluphenazine) Provides Off-Label Drug Candidates","author":"Jilan Nazeam, Esraa Z. Mohammed, Mariam Raafat, Mariam Houssein, Asmaa Elkafoury, Dina Hamdy, Lina Jamil","doi":"10.1177\/2472555220950236","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of pandemic coronavirus disease 2019 (COVID-19). So far, no approved therapy has been developed to halt the spread of the pathogen, and unfortunately, the strategies for developing a new therapy will require a long time and very extensive resources. Therefore, drug repurposing has emerged as an ideal strategy toward a smart, versatile, quick way to confine the lethal disease. In this endeavor, natural products have been an untapped source for new drugs. This review represents the confederated experience of multidisciplinary researchers of 99 articles using several databases: Google Scholar, Science Direct, MEDLINE, Web of Science, Scopus, and PubMed. To establish the hypothesis, a Bayesian perspective of a systematic review was used to outline evidence synthesis. Our docking documentation of 69 compounds and future research agenda assumptions were directed toward finding an effective and economic anti-COVID-19 treatment from natural products. Glucosinolate, flavones, and sulfated nitrogenous compounds demonstrate direct anti-SARS-CoV-2 activity through inhibition protease enzymes and may be considered potential candidates against coronavirus. These findings could be a starting point to initiate an integrative study that may encompass interested scientists and research institutes to test the hypothesis in vitro, in vivo, and in clinics after satisfying all ethical requirements.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":523,"name":"Pharmacokinetics\/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK\/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents","author":"Markus Zeitlinger, Birgit C. P. Koch, Roger Bruggemann, Pieter De Cock, Timothy Felton, Maya Hites, Jennifer Le, Sonia Luque, Alasdair P. MacGowan, Deborah J. E. Marriott, Anouk E. Muller, Kristina Nadrah, David L. Paterson, Joseph F. Standing, Jo\u00e3o P. Telles, Michael W\u00f6lfl-Duchek, Michael Thy, Jason A. Roberts","doi":"10.1007\/s40262-020-00924-9","abstract":"There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug\u2013drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir\/ritonavir (LPV\/r) plus ribavirin; and strong evidence for LPV\/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":522,"name":"Non\u2010steroidal anti\u2010inflammatory drugs, prostaglandins, and COVID\u201019","author":"Calum T. Robb, Marie Goepp, Adriano G. Rossi, Chengcan Yao","doi":"10.1111\/bph.15206","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) is the cause of the novel coronavirus disease 2019 (COVID\u201019), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID\u201019. Non\u2010steroidal anti\u2010inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID\u201019 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti\u2010inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS\u2010CoV\u20102 infection and the development and progression of COVID\u201019.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":521,"name":"Old Drugs for a New Virus: Repurposed Approaches for Combating COVID-19","author":"Sirle Saul, Shirit Einav","doi":"10.1021\/acsinfecdis.0c00343","abstract":"There is a large global unmet need for effective countermeasures to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). The development of novel antiviral drugs is expensive and too slow to meet the immediate need. The repurposing of drugs that are approved or are under advanced clinical investigation provides a cost- and time-effective therapeutic solution. This review summarizes the major repurposed approaches that have been proposed or are already being studied in clinical trials for COVID-19. Among these approaches are drugs that aim to reduce SARS-CoV-2 replication by targeting either viral enzymatic functions or cellular factors required for the viral life cycle. Drugs that modulate the host immune response to SARS-CoV-2 infection by boosting it to enhance viral clearance or by suppressing it to prevent excessive inflammation and tissue injury represent another category. Lastly, we discuss means to discover repurposed drugs and the ongoing challenges associated with the off-label use of existing drugs in the context of the COVID-19 outbreak.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":520,"name":"Inhibition of SARS-CoV-2 entry through the ACE2\/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies","author":"Georgia Ragia, Vangelis G. Manolopoulos ","doi":"10.1007\/s00228-020-02963-4","abstract":"Aim\r\nThe COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells.\r\n\r\nMethod\r\nWe scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin.\r\n\r\nResults\r\nSeveral drugs\/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil).\r\n\r\nConclusion\r\nSeveral agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":519,"name":"Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials","author":"David A Jolliffe, Carlos A Camargo Jr, John D Sluyter, Mary Aglipay, John F Aloia, Davaasambuu Ganmaa, Peter Bergman, Arturo Borzutzky, Camilla T Damsgaard, Gal Dubnov-Raz, Susanna Esposito, Clare Gilham, Adit A Ginde, Inbal Golan-Tripto, Emma C Goodall, Cameron C Grant, Christopher J Griffiths, Anna Maria Hibbs, Wim Janssens, Anuradha Vaman Khadilkar, Ilkka Laaksi, Margaret T Lee, Mark Loeb, Jonathon L Maguire, Pawe\u0142 Majak, David T Mauger, Semira Manaseki-Holland, David R Murdoch, Akio Nakashim","doi":"10.1101\/2020.07.14.20152728","abstract":"Background A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed.\r\n\r\nMethods Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633).\r\n\r\nFindings We identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of \u226412 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger\u2019s test).\r\n\r\nInterpretation Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.","type":"Review","database":"MedRxiv","created":"2021-01-31"},{"id":518,"name":"Mesenchymal Stem Cell Derived Exosomes: a Nano Platform for Therapeutics and Drug Delivery in Combating COVID-19","author":"Pinky, Suchi Gupta, Vishnu Krishnakumar, Yashvi Sharma, Amit Kumar Dinda, Sujata Mohanty ","doi":"10.1007\/s12015-020-10002-z","abstract":"The recent pandemic situation transpired due to coronavirus novel strain SARS-CoV-2 has become a global concern. This human coronavirus (HCov-19) has put the world on high alert as the numbers of confirmed cases are continuously increasing. The world is now fighting against this deadly virus and is leaving no stone unturned to find effective treatments through testing of various available drugs, including those effective against flu, malaria, etc. With an urgent need for the development of potential strategies, two recent studies from China using Mesenchymal Stem Cells (MSCs) to treat COVID-19 pneumonia have shed some light on a potential cure for the COVID-19 infected patients. However, MSCs, despite being used in various other clinical trials have always been questioned for their tendency to aggregate or form clumps in the injured or disease microenvironment. It has also been reported in various studies that exosomes secreted by these MSCs, contribute towards the cell\u2019s biological and therapeutic efficacy. There have been reports evaluating the safety and feasibility of these exosomes in various lung diseases, thereby proposing them as a cell-free therapeutic agent. Also, attractive features like cell targeting, low-immunogenicity, safety, and high biocompatibility distinguish these exosomes from other synthetic nano-vesicles and thus potentiate their role as a drug delivery nano-platform. Building upon these observations, herein, efforts are made to give an overview of stem cell-derived exosomes as an appealing therapeutic agent and drug delivery nano-carrier. In this review, we briefly recapitulate the recent evidence and developments in understanding exosomes as a promising candidate for novel nano-intervention in the current pandemic scenario. Furthermore, this review will highlight and discuss mechanistic role of exosomes to combat severe lung pathological conditions. We have also attempted to dwell into the nano-formulation of exosomes for its better applicability, storage, and stability thereby conferring them as off the shelf therapeutic.","type":"Review","database":"MedRxiv","created":"2021-01-31"},{"id":517,"name":"Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2\u2009S protein and human ACE2 interaction through virtual screening approaches","author":"Hourieh Kalhor, Solmaz Sadeghi, Hoda Abolhasani, Reyhaneh Kalhor, Hamzeh Rahimi","doi":"10.1080\/07391102.2020.1824816","abstract":"Most recently, the new coronavirus (SARS-CoV-2) has been recognized as a pandemic by the World Health Organization (WHO) while this virus shares substantial similarity with SARS-CoV. So far, no definitive vaccine or drug has been developed to cure Covid-19 disease, since many important aspects about Covid-19 such as pathogenesis and proliferation pathways are still unclear. It was proven that human ACE2 is the main receptor for the entry of Covid-19 into lower respiratory tract epithelial cells through interaction with SARS-CoV-2\u2009S protein. Based on this observation, it is expected that the virus infection can be inhibited if protein-protein interaction is prevented. In this study, using structure-based virtual screening of FDA databases, several lead drugs were discovered based on the ACE2-binding pocket of SARS-CoV-2\u2009S protein. Then, binding affinity, binding modes, critical interactions, and pharmaceutical properties of the lead drugs were evaluated. Among the previously approved drugs, Diammonium Glycyrrhizinate, Digitoxin, Ivermectin, Rapamycin, Rifaximin, and Amphotericin B represented the most desirable features, and can be possible candidates for Covid-19 therapies. Furthermore, molecular dynamics (MD) simulation was accomplished for three S protein\/drug complexes with the highest binding affinity and best conformation and binding free energies were also computed with the Molecular Mechanics\/Poisson\u2013Boltzmann Surface Area (MM\/PBSA) method. Results demonstrated the stable binding of these compounds to the S protein; however, in order to confirm the curative effect of these drugs, clinical trials must be done.","type":"Research","database":"PubMed","created":"2021-01-31"},{"id":516,"name":"A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19","author":"Xuping Xie, Antonio E. Muruato, Xianwen Zhang, Kumari G. Lokugamage, Camila R. Fontes-Garfias, Jing Zou, Jianying Liu, Ping Ren, Mini Balakrishnan, Tomas Cihlar, Chien-Te K. Tseng, Shinji Makino, Vineet D. Menachery, John P. Bilello, Pei-Yong Shi","doi":"10.1101\/2020.06.22.165712","abstract":"A high-throughput platform would greatly facilitate COVID-19 serological testing and antiviral screening. Here we report a nanoluciferase SARS-CoV-2 (SARS-CoV-2-Nluc) that is genetically stable and replicates similarly to the wild-type virus in cell culture. We demonstrate that the optimized reporter virus assay in Vero E6 cells can be used to measure neutralizing antibody activity in patient sera and produces results in concordance with a plaque reduction neutralization test (PRNT). Compared with the low-throughput PRNT (3 days), the SARS-CoV-2-Nluc assay has substantially shorter turnaround time (5 hours) with a high-throughput testing capacity. Thus, the assay can be readily deployed for large-scale vaccine evaluation and neutralizing antibody testing in humans. Additionally, we developed a high-throughput antiviral assay using SARS-CoV-2-Nluc infection of A549 cells expressing human ACE2 receptor (A549-hACE2). When tested against this reporter virus, remdesivir exhibited substantially more potent activity in A549-hACE2 cells compared to Vero E6 cells (EC50 0.115 vs 1.28 \u03bcM), while this difference was not observed for chloroquine (EC50 1.32 vs 3.52 \u03bcM), underscoring the importance of selecting appropriate cells for antiviral testing. Using the optimized SARS-CoV-2-Nluc assay, we evaluated a collection of approved and investigational antivirals and other anti-infective drugs. Nelfinavir, rupintrivir, and cobicistat were identified as the most selective inhibitors of SARS-CoV-2-Nluc (EC50 0.77 to 2.74 \u03bcM). In contrast, most of the clinically approved antivirals, including tenofovir alafenamide, emtricitabine, sofosbuvir, ledipasvir, and velpatasvir were inactive at concentrations up to 10 \u03bcM. Collectively, this high-throughput platform represents a reliable tool for rapid neutralization testing and antiviral screening for SARS-CoV-2.","type":"Research","database":"BioRxiv","created":"2021-01-31"},{"id":515,"name":"While We Wait for a Vaccine Against SARS-CoV-2, Why Not Think About Available Drugs?","author":"Francisco J. Barrantes","doi":"10.3389\/fphys.2020.00820","abstract":"At the time of reception of this article (April 2, 2020), efforts to develop a specific vaccine against SARS-Cov-2, the causative agent of the coronavirus disease 2019 (COVID-19), had just begun trial phase 1, but full validation of this and other current developments is likely to take many more months to reach completion. The ongoing pandemic constitutes a major health burden of world proportions that is also having a devastating impact on whole economies worldwide, the knock-on effects of which could be catastrophic especially in poorer countries. Alternative measures to ameliorate the impact and hamper or minimally slow down disease progression are urgently called for. This review discusses past and currently evolving data on the etiological agent of the current pandemic, SARS-CoV-2, and its host cell receptors with a view to disclosing alternative drugs for palliative or therapeutic approaches. Firstly, SARS-CoV-2 exhibits marked tropism for cells that harbor the membrane-bound metalloprotease angiotensin-converting enzyme 2 (ACE2) at their plasmalemma, predominantly in cells lining the oral cavity, upper respiratory tract, and bronchoalveolar cells, making these epithelial mucosae the most likely viral receptor cell targets and entry routes. Secondly, the crystal structures of several coronavirus spike proteins in complex with their cell host target receptors, and of SARS-Cov-2 in complex with an inhibitor, are now available at atomic resolution through X-ray diffraction and cryo-electron microscopy studies. Thirdly, viral entry of other viruses has been successfully blocked by inhibiting viral endogenous proteases or clathrin\/dynamin-dependent endocytosis, the same internalization pathway followed by ACE2 and some viruses. Fourthly, the target cell-surface receptor molecules and SARS-CoV-2 possess other putative sites for drugs potentially modulating receptor activity or virus processing. A multi-pronged pharmacological approach attacking more than one flank of the viral-receptor interactions is worth considering as a front-line strategy.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":514,"name":"Recent insights for the emerging COVID-19: Drug discovery, therapeutic options and vaccine development","author":"Yuefei Zhu, Jia Lic, Zhiqing Pang","doi":"10.1016\/j.ajps.2020.06.001","abstract":"SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population, causing over 5.5 million confirmed cases worldwide. As COVID-19 has posed a global threat with significant human casualties and severe economic losses, there is a pressing demand to further understand the current situation and develop rational strategies to contain the drastic spread of the virus. Although there are no specific antiviral therapies that have proven effective in randomized clinical trials, currently, the rapid detection technology along with several promising therapeutics for COVID-19 have mitigated its drastic transmission. Besides, global institutions and corporations have commenced to parse out effective vaccines for the prevention of COVID-19. Herein, the present review will give exhaustive details of extensive researches concerning the drug discovery and therapeutic options for COVID-19 as well as some insightful discussions of the status of COVID-19.","type":"Research","database":"PubMed","created":"2021-01-31"},{"id":513,"name":"Drug targets for COVID-19 therapeutics: Ongoing global efforts","author":"Ambrish Saxena ","doi":"10.12122\/j.issn.1673-4254.2020.03.07","abstract":"The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARS-CoV-2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":512,"name":"Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19","author":"Carmen Mirabelli, Jesse W. Wotring, Charles J. Zhang, Sean M. McCarty, Reid Fursmidt, Tristan Frum, Namrata S. Kadambi, Anya T. Amin, Teresa R. O\u2019Meara, Carla D. Pretto, Jason R. Spence, Jessie Huang, Konstantinos D. Alysandratos, Darrell N. Kotton, Samuel K. Handelman, Christiane E. Wobus, Kevin J. Weatherwax, George A. Mashour, Matthew J. O\u2019Meara, Jonathan Z. Sexton","doi":"10.1101\/2020.05.27.117184","abstract":"The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10-15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 17 dose-responsive compounds with in vitro antiviral efficacy in human liver Huh7 cells and confirmed antiviral efficacy in human colon carcinoma Caco-2, human prostate adenocarcinoma LNCaP, and in a physiologic relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras\/Raf\/MEK\/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein classically found in secretory fluids, including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.","type":"Research","database":"BioRxiv","created":"2021-01-31"},{"id":511,"name":"A Double-Edged Sword\u2014Cardiovascular Concerns of Potential Anti-COVID-19 Drugs","author":"Wen-Liang Yu, Han Siong Toh, Chia-Te Liao, Wei-Ting Chang ","doi":"10.1007\/s10557-020-07024-7","abstract":"Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 significantly affects multiple systems including the cardiovascular system. Most importantly, in addition to the direct injury from the virus per se, the subsequent cytokine storm, an overproduction of immune cells and their activating compounds, causes devastating damage. To date, emerging anti-SARS-CoV-2 treatments are warranted to control epidemics. Several candidate drugs have been screened and are currently under investigation. These primarily include antiviral regimens and immunomodulatory regimens. However, beyond the anti-SARS-CoV-2 effects, these drugs may also have risks to the cardiovascular system, especially altering cardiac conduction. Herein, we review the cardiovascular risks of potential anti-COVID-19 drugs.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":510,"name":"Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks","author":"Salvatore Crisafulli, Valentina Isgr\u00f2, Laura La Corte, Fabiola Atzeni, Gianluca Trifir\u00f2 ","doi":"10.1007\/s40259-020-00430-1","abstract":"The epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. This public health emergency has triggered a race to find medications to improve the prognosis of this disease. There is currently great interest in drug repositioning to manage SARS-CoV-2 infection, that is, the evaluation of the potential benefits of a drug that has already been proven safe and effective in humans for other approved indications. As interleukin-6 (IL-6) acts as a key driver of the inflammation associated with coronavirus disease 2019 (COVID-19), IL-6 and IL-6 receptor (IL-6R) inhibition appear to be promising targets for the treatment of COVID-19 patients. It is important to critically analyze the available evidence concerning the use of the available anti-IL-6 (siltuximab) and anti-IL-6R (tocilizumab and sarilumab) agents in COVID-19 patients, in terms of both benefit and risk. In this review, the pathogenesis of the cytokine storm induced by COVID-19, the role of IL-6 in this cytokine storm, the rationale for the use of anti-IL-6 agents, and key information on potential benefits and safety monitoring of these biologicals in COVID-19 patients is discussed.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":509,"name":"Virtual screening, ADME\/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19","author":"Lorane Izabel da SilvaHage-Melim, Leonardo Bruno Federico, Nayana Keyla Seabra de Oliveira, Viviane Cristina Cardoso Francisco, Lenir Cabral Correia, Henrique Barrosde Lima, Suzane Quintana Gomes, Mariana Pegrucci Barcelos, Isaque Ant\u00f4nio Galindo Francischini, Carlos Henrique Tomich de Paula da Silva","doi":"10.1016\/j.lfs.2020.117963","abstract":"The new Coronavirus (SARS-CoV-2) is the cause of a serious infection in the respiratory tract called COVID-19. Structures of the main protease of SARS-CoV-2 (Mpro), responsible for the replication of the virus, have been solved and quickly made available, thus allowing the design of compounds that could interact with this protease and thus to prevent the progression of the disease by avoiding the viral peptide to be cleaved, so that smaller viral proteins can be released into the host's plasma. These structural data are extremely important for in silico design and development of compounds as well, being possible to quick and effectively identify potential inhibitors addressed to such enzyme's structure. Therefore, in order to identify potential inhibitors for Mpro, we used virtual screening approaches based with the structure of the enzyme and two compounds libraries, targeted to SARS-CoV-2, containing compounds with predicted activity against Mpro. In this way, we selected, through docking studies, the 100 top-ranked compounds, which followed to subsequent studies of pharmacokinetic and toxicity predictions. After all the simulations and predictions here performed, we obtained 10 top-ranked compounds that were again in silico analyzed inside the Mpro catalytic site, together some drugs that are being currently investigated for treatment of COVID-19. After proposing and analyzing the interaction modes of these compounds, we submitted one molecule then selected as template to a 2D similarity study in a database containing drugs approved by FDA and we have found and indicated Apixaban as a potential drug for future treatment of COVID-19.","type":"Research","database":"PubMed","created":"2021-01-31"},{"id":508,"name":"Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: Insights from structures of protease and inhibitors","author":"Jun He, Lijun Hu, Xiaojun Huang, Chenran Wang, Zhimin Zhang, Ying Wang, Dongmei Zhang, Wencai Ye","doi":"10.1016\/j.ijantimicag.2020.106055","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which belong to the same Betacoronavirus genus, induces severe acute respiratory disease that is a threat to human health. Since the outbreak of infection by SARS-CoV-2 began, which causes coronavirus disease 2019 (COVID-19), the disease has rapidly spread worldwide. Thus, a search for effective drugs able to inhibit SARS-CoV-2 has become a global pursuit. The 3C-like protease (3CLpro), which hydrolyses viral polyproteins to produce functional proteins, is essential for coronavirus replication and is considered an important therapeutic target for diseases caused by coronaviruses, including COVID-19. Many 3CLpro inhibitors have been proposed and some new drug candidates have achieved success in preclinical studies. In this review, we briefly describe recent developments in determining the structure of 3CLpro and its function in coronavirus replication and summarise new insights into 3CLpro inhibitors and their mechanisms of action. The clinical application prospects and limitations of 3CLpro inhibitors for COVID-19 treatment are also discussed.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":507,"name":"In Silico Evaluation of Prospective Anti-COVID-19 Drug Candidates as Potential SARS-CoV-2 Main Protease Inhibitors","author":"Mahmoud A. A. Ibrahim, Alaa H. M. Abdelrahman, Khaled S. Allemailem, Ahmad Almatroudi, Mahmoud F. Moustafa, Mohamed-Elamir F. Hegazy ","doi":"10.1007\/s10930-020-09945-6","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emanating human infectious coronavirus that causes COVID-19 disease. On 11th March 2020, it has been announced as a pandemic by the World Health Organization (WHO). Recently, several repositioned drugs have been subjected to clinical investigations as anti-COVID-19 drugs. Here, in silico drug discovery tools were utilized to evaluate the binding affinities and features of eighteen anti-COVID-19 drug candidates against SARS-CoV-2 main protease (Mpro). Molecular docking calculations using Autodock Vina showed considerable binding affinities of the investigated drugs with docking scores ranging from\u2009\u2212\u20095.3 to\u2009\u2212\u20098.3 kcal\/mol, with higher binding affinities for HIV drugs compared to the other antiviral drugs. Molecular dynamics (MD) simulations were performed for the predicted drug-Mpro complexes for 50 ns, followed by binding energy calculations utilizing molecular mechanics-generalized Born surface area (MM-GBSA) approach. MM-GBSA calculations demonstrated promising binding affinities of TMC-310911 and ritonavir towards SARS-CoV-2 Mpro, with binding energy values of\u2009\u2212\u200952.8 and\u2009\u2212\u200949.4 kcal\/mol, respectively. Surpass potentialities of TMC-310911 and ritonavir are returned to their capabilities of forming multiple hydrogen bonds with the proximal amino acids inside Mpro's binding site. Structural and energetic analyses involving root-mean-square deviation, binding energy per-frame, center-of-mass distance, and hydrogen bond length demonstrated the stability of TMC-310911 and ritonavir inside the Mpro's active site over the 50 ns MD simulation. This study sheds light on HIV protease drugs as prospective SARS-CoV-2 Mpro inhibitors.","type":"Research","database":"PubMed","created":"2021-01-31"},{"id":506,"name":"Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19","author":"Wen Cui, Kailin Yang, Haitao Yang","doi":"10.3389\/fmolb.2020.616341","abstract":"The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) rapidly turned into an unprecedented pandemic of coronavirus disease 2019 (COVID-19). This global healthcare emergency marked the third occurrence of a deadly coronavirus (CoV) into the human society after entering the new millennium, which overwhelmed the worldwide healthcare system and affected the global economy. However, therapeutic options for COVID-19 are still very limited. Developing drugs targeting vital proteins in viral life cycle is a feasible approach to overcome this dilemma. Main protease (Mpro) plays a dominant role in processing CoV-encoded polyproteins which mediate the assembly of replication-transcription machinery and is thus recognized as an ideal antiviral target. Here we summarize the recent progress in the discovery of anti-SARS-CoV-2 agents against Mpro. Combining structural study, virtual screen, and experimental screen, numerous therapeutic candidates including repurposed drugs and ab initio designed compounds have been proposed. Such collaborative effort from the scientific community would accelerate the pace of developing efficacious treatment for COVID-19.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":505,"name":"Pharmacogenomics of genetic polymorphism within the genes responsible for SARS\u2010CoV\u20102 susceptibility and the drug\u2010metabolising genes used in treatment","author":"Laith N. AL\u2010Eitan, Saif Z. Alahmad","doi":"10.1002\/rmv.2194","abstract":"The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side\u2010effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS\u2010CoV\u20102 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug\u2010metabolising enzyme genes of several selected drugs used in the treatment of COVID\u201019 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high\u2010throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":504,"name":"Quinacrine, an Antimalarial Drug with Strong Activity Inhibiting SARS-CoV-2 Viral Replication In Vitro","author":"M\u00f3nica Salas Rojas, Ra\u00fal Silva Garcia, Estela Bini, Ver\u00f3nica P\u00e9rez de la Cruz, Juan Carlos Le\u00f3n Contreras, Rogelio Hern\u00e1ndez Pando, Fernando Bastida Gonzalez, Eduardo Davila-Gonzalez, Mario Orozco Morales, Armando Gamboa Dom\u00ednguez, Julio Sotelo, Benjam\u00edn Pineda","doi":"10.3390\/v13010121","abstract":"Quinacrine (Qx), a molecule used as an antimalarial, has shown anticancer, antiprion, and antiviral activity. The most relevant antiviral activities of Qx are related to its ability to raise pH in acidic organelles, diminishing viral enzymatic activity for viral cell entry, and its ability to bind to viral DNA and RNA. Moreover, Qx has been used as an immunomodulator in cutaneous lupus erythematosus and various rheumatological diseases, by inhibiting phospholipase A2 modulating the Th1\/Th2 response. The aim of this study was to evaluate the potential antiviral effect of Qx against denominated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Vero E6 cells. The cytotoxicity of Qx in Vero E6 cells was determined by the MTT assay. Afterwards, Vero E6 cells were infected with SARS-CoV-2 at different multiplicities of infections (MOIs) of 0.1 and 0.01 in the presence of Qx (0\u201330 \u00b5M) to determinate the half maximal effective concentration (EC50). After 48 h, the effect of Qx against SARS-CoV-2 was assessed by viral cytotoxicity and viral copy numbers, the last were determined by digital real-time RT-PCR (ddRT-PCR). Additionally, electron and confocal microscopy of Vero E6 cells infected and treated with Qx was studied. Our data show that Qx reduces SARS-CoV-2 virus replication and virus cytotoxicity, apparently by inhibition of viral ensemble, as observed by ultrastructural images, suggesting that Qx could be a potential drug for further clinical studies against coronavirus disease 2019 (COVID-19) infection.","type":"Research","database":"PubMed","created":"2021-01-31"},{"id":503,"name":"Perspective on the Role of Antibodies and Potential Therapeutic Drugs to Combat COVID-19","author":"Siddhi Tandon, Anchal Aggarwal, Shubhra Jain, Sanjay Shukla, Sarika Chaudhary ","doi":"10.1007\/s10930-020-09921-0","abstract":"The sudden emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease of 2019 (COVID-19) has brought the world to a standstill. Thousands of people across the globe are biting the dust with every passing day and yet more are being tested positive for the SARS-CoV-2 infection. In order to dispense this current crisis, numerous treatment options have been tried and tested and many more are still under scrutiny. The development of vaccines may help in the prevention of the global pandemic, however, there is still a need for the development of alternate approaches to combat the disease. In this review we highlight the new discoveries and furtherance in the antibody based therapeutic options and the potent drugs, with special emphasis on the development of the monoclonal and polyclonal antibodies and the repurposed drugs, which may prove to be of significant importance for the treatment of COVID-19, in the days to come. It is an attempt to evaluate the currently presented challenges so as to provide a scope for the ongoing research and assistance in the development of the effective therapeutic options against SARS-CoV-2.","type":"Review","database":"PubMed","created":"2021-01-31"},{"id":502,"name":"Overview of Targets and Potential Drugs of SARS-CoV-2 According to the Viral Replication","author":"Yi Zhang, Liang V. Tang","doi":"10.1021\/acs.jproteome.0c00526","abstract":"Since the novel coronavirus pandemic, people around the world have been touched in varying degrees, and this pandemic has raised a major global health concern. As there is no effective drug or vaccine, it is urgent to find therapeutic drugs that can serve to deal with the current epidemic situation in all countries and regions. We searched drugs and response measures for SARS-CoV-2 in the PubMed database, and then updated the potential targets and therapeutic drugs from the perspective of the viral replication cycle. The drug research studies of the viral replication cycle are predominantly focused on the process of the virus entering cells, proteases, and RdRp. The inhibitors of the virus entry to cells and RdRp, such as Arbidol, remdesivir, favipiravir, EIDD-2081, and ribavirin, are in clinical trials, while most of the protease inhibitors are mainly calculated by molecular docking technology, which needs in vivo and in vitro experiments to prove the effect for SARS-CoV-2. This review summarizes the drugs targeting the viral replication process and provides a basis and directions for future drug development and reuse on the protein level of COVID-19.","type":"Review","database":"PubMed","created":"2021-01-26"},{"id":501,"name":"High-Throughput Screening of an FDA-Approved Drug Library Identifies Inhibitors against Arenaviruses and SARS-CoV-2","author":"Weiwei Wan, Shenglin Zhu, Shufen Li, Weijuan Shang, Ruxue Zhang, Hao Li, Wei Liu, Gengfu Xiao, Ke Peng, Leike Zhang","doi":"10.1021\/acsinfecdis.0c00486","abstract":"Arenaviruses are a large family of enveloped negative-strand RNA viruses that include several causative agents of severe hemorrhagic fevers. Currently, there are no FDA-licensed drugs to treat arenavirus infection except for the off-labeled use of ribavirin. Here, we performed antiviral drug screening against the Old World arenavirus lymphocytic choriomeningitis virus (LCMV) using an FDA-approved drug library. Five drug candidates were identified, including mycophenolic acid, benidipine hydrochloride, clofazimine, dabrafenib, and apatinib, for having strong anti-LCMV effects. Further analysis indicated that benidipine hydrochloride inhibited LCMV membrane fusion, and an adaptive mutation on the LCMV glycoprotein D414 site was found to antagonize the anti-LCMV activity of benidipine hydrochloride. Mycophenolic acid inhibited LCMV replication by depleting GTP production. We also found mycophenolic acid, clofazimine, dabrafenib, and apatinib can inhibit the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Owing to their FDA-approved status, these drug candidates can potentially be used rapidly in the clinical treatment of arenavirus and SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2021-01-18"},{"id":500,"name":"Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study","author":"Prateek Kumar, Taniya Bhardwaj, Ankur Kumar, Bhuvaneshwari R. Gehi, Shivani K. Kapuganti, Neha Garg, Gopal Nath, Rajanish Giri","doi":"10.1080\/07391102.2020.1845976","abstract":"Given the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as Mpro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting Mpro, we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of Mpro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 Mpro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500\u2009ns where these drugs show stable binding with Mpro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2.","type":"Research","database":"PubMed","created":"2021-01-18"},{"id":499,"name":"Drug Weaponry to Fight Against SARS-CoV-2","author":"Elena Cabez\u00f3n, Ignacio Arechaga","doi":"10.3389\/fmolb.2020.00204","abstract":"The current outbreak of SARS-CoV-2 virus has caused a large increase in mortality and morbidity associated with respiratory diseases. Huge efforts are currently ongoing to develop a vaccine against this virus. However, alternative approaches could be considered in the fight against this disease. Among other strategies, structural-based drug design could be an effective approach to generate specific molecules against SARS-CoV-2, thus reducing viral burden in infected patients. Here, in addition to this structural approach, we also revise several therapeutic strategies to fight against this viral threat. Furthermore, we report ACE-2 genetic polymorphic variants affecting residues involved in close contacts with SARS-CoV-2 that might be associated to different infection risks. These analyses could provide valuable information to predict the course of the disease.","type":"Review","database":"PubMed","created":"2021-01-18"},{"id":498,"name":"Cardiovascular Active Peptides of Marine Origin with ACE Inhibitory Activities: Potential Role as Anti-Hypertensive Drugs and in Prevention of SARS-CoV-2 Infection","author":"Marco Festa, Clementina Sansone, Christophe Brunet, Fabio Crocetta, Luisa Di Paola, Michele Lombardo, Antonino Bruno, Douglas M. Noonan, Adriana Albini","doi":"10.3390\/ijms21218364","abstract":"Growing interest in hypertension\u2014one of the main factors characterizing the cardiometabolic syndrome (CMS)\u2014and anti-hypertensive drugs raised from the emergence of a new coronavirus, SARS-CoV-2, responsible for the COVID19 pandemic. The virus SARS-CoV-2 employs the Angiotensin-converting enzyme 2 (ACE2), a component of the RAAS (Renin-Angiotensin-Aldosterone System) system, as a receptor for entry into the cells. Several classes of synthetic drugs are available for hypertension, rarely associated with severe or mild adverse effects. New natural compounds, such as peptides, might be useful to treat some hypertensive patients. The main feature of ACE inhibitory peptides is the location of the hydrophobic residue, usually Proline, at the C-terminus. Some already known bioactive peptides derived from marine resources have potential ACE inhibitory activity and can be considered therapeutic agents to treat hypertension. Peptides isolated from marine vertebrates, invertebrates, seaweeds, or sea microorganisms displayed important biological activities to treat hypertensive patients. Here, we reviewed the anti-hypertensive activities of bioactive molecules isolated\/extracted from marine organisms and discussed the associated molecular mechanisms involved. We also examined ACE2 modulation in sight of SARS2-Cov infection prevention.","type":"Review","database":"PubMed","created":"2021-01-18"},{"id":497,"name":"Identifying Effective Antiviral Drugs Against SARS-CoV-2 by Drug Repositioning Through Virus-Drug Association Prediction","author":"Lihong Peng, Xiongfei Tian, Ling Shen, Ming Kuang, Tianbao Li, Geng Tian, Jialiang Yang, Liqian Zhou","doi":"10.3389\/fgene.2020.577387","abstract":"A new coronavirus called SARS-CoV-2 is rapidly spreading around the world. Over 16,558,289 infected cases with 656,093 deaths have been reported by July 29th, 2020, and it is urgent to identify effective antiviral treatment. In this study, potential antiviral drugs against SARS-CoV-2 were identified by drug repositioning through Virus-Drug Association (VDA) prediction. 96 VDAs between 11 types of viruses similar to SARS-CoV-2 and 78 small molecular drugs were extracted and a novel VDA identification model (VDA-RLSBN) was developed to find potential VDAs related to SARS-CoV-2. The model integrated the complete genome sequences of the viruses, the chemical structures of drugs, a regularized least squared classifier (RLS), a bipartite local model, and the neighbor association information. Compared with five state-of-the-art association prediction methods, VDA-RLSBN obtained the best AUC of 0.9085 and AUPR of 0.6630. Ribavirin was predicted to be the best small molecular drug, with a higher molecular binding energy of \u22126.39 kcal\/mol with human angiotensin-converting enzyme 2 (ACE2), followed by remdesivir (\u22127.4 kcal\/mol), mycophenolic acid (\u22125.35 kcal\/mol), and chloroquine (\u22126.29 kcal\/mol). Ribavirin, remdesivir, and chloroquine have been under clinical trials or supported by recent works. In addition, for the first time, our results suggested several antiviral drugs, such as FK506, with molecular binding energies of \u221211.06 and \u221210.1 kcal\/mol with ACE2 and the spike protein, respectively, could be potentially used to prevent SARS-CoV-2 and remains to further validation. Drug repositioning through virus\u2013drug association prediction can effectively find potential antiviral drugs against SARS-CoV-2.","type":"Research","database":"PubMed","created":"2021-01-18"},{"id":496,"name":"An overview of antiviral strategies for coronavirus 2 (SARS\u2010CoV\u20102) infection with special reference to antimalarial drugs chloroquine and hydroxychloroquine","author":"Viktorija Dragojevic Simic,  Milijana Miljkovic,  Dusica Stamenkovic,  Berislav Vekic,  Nenad Ratkovic,  Radoje Simic,  Nemanja Rancic","doi":"https:\/\/doi.org\/10.1111\/ijcp.13825","abstract":"At present, neither specific antiviral drugs, nor vaccine is recommended for coronavirus disease 2019 (COVID\u201019) treatment. In this review we discuss the drugs suggested as therapy for COVID\u201019 infection, with a focus on chloroquine and hydroxychloroquine. The list of drugs used for COVID\u201019 treatment includes a combination of lopinavir and ritonavir, remdesivir, favipiravir, alpha\u2010interferon, ribavirin, atazanavir, umifenovir, and tocilizumab. As their efficacy and safety are under investigation, none of the regulatory agencies approved them for the treatment of COVID\u201019 infection. Although chloroquine and hydroxychloroquine possess antiviral and immunomodulatory effects, in practice benefit of their use for COVID\u201019 treatment is controversial. Several studies investigating hydroxychloroquine were stopped and the French national medicines regulator suspended its use in clinical trials because of safety concerns. The results from the double\u2010blind, randomised clinical trials, including large number of participants, will add better insight into the role of these two drugs as already available and affordable, antimalarial therapy. The ethical issue on emergency use of chloroquine and hydroxychloroquine in the settings of COVID\u201019 should be carefully managed, with adherence to the \u201cmonitored emergency use of unregistered and experimental interventions\u201d (MEURI) framework or be ethically approved as a trial, as stated by the WHO. Potential shortage of chloroquine\/hydroxychloroquine on the market can be overbridged with regular prescriptions by medical doctors and national drug agency should ensure sufficient quantities of these drugs for standard indications.","type":"Review","database":"PubMed","created":"2021-01-18"},{"id":495,"name":"Natural Products: A Rich Source of Antiviral Drug Lead Candidates for the Management of COVID-19","author":"Yasanandana Supunsiri Wijayasinghe, Pravin Bhansali, Ronald E. Viola, Mohammad A. Kamal, Nitesh Kumar Poddar","doi":"10.2174\/1381612826666201118111151","abstract":"Today, the world is suffering from the pandemic of a novel coronavirus disease (COVID-19), a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic is the third fatal coronavirus outbreak that has already occurred in the 21st century. Even six months after its emergence, hundreds of thousands of people are still being infected with SARS-CoV-2, and thousands of lives are lost every day across the world. No effective therapy has been approved to date for the prevention or treatment of this disease, suggesting the need to broaden the scope in the search for effective treatments. Throughout history, folk medicine has been successfully used to treat various ailments in humans and Traditional Chinese Medicine has been instrumental in the containment of a number of viral diseases. Owing to their high chemical diversity and safety profiles, natural products offer great promises as potentially effective antiviral drugs. In recent years, a large number of anti-coronaviral phytochemicals with different mechanisms of action have been identified. Among them, tetra-O-galloyl-\u03b2-D-glucose, caffeic acid, and saikosaponin B2 block viral entry. A number of flavonoids inhibit viral proteases. Silvestrol inhibits protein synthesis. Myricetin and scutellarein inhibit viral replication. Emodin, luteolin, and quercetin demonstrate anti-coronaviral activity by inhibiting multiple processes in the virus life cycle. In this review, we critically evaluate the findings of the natural product-based anti-coronaviral research that has been published during last two decades, and attempt to provide a comprehensive description about their utility as potential broad-spectrum anti-coronaviral drugs, examining leads that may guide\/facilitate anti-SARS-CoV-2 drug development studies.","type":"Review","database":"PubMed","created":"2021-01-18"},{"id":494,"name":"An effective drug against COVID-19: reality or dream?","author":"Atieh Yaghoubi, Saeid Amel Jamehdar, Aref Movaqar, Nasrin Milani, Saman Soleimanpour ","doi":"10.1080\/17476348.2021.1854092","abstract":"Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is well known as a novel member of the coronavirus family which caused a sudden outbreak of Coronavirus disease-2019 (COVID-19) in China that quickly developed into a global pandemic. No effective approaches are found as yet for the therapy and epidemiological control of this new virus. We searched the literature in PubMed, Scopus, Web of Knowledge, Google Scholar, and MeSH, for articles and abstracts describing SARS-CoV-2, COVID-19, pneumonia, clinical trials, drug, treatment, and medicine.\r\n\r\nAreas covered: The present study aimed to comprehensively overview the current literature on effective anti-SARS-CoV-2 drugs.\r\n\r\nExpert opinion: Since the beginning of this pandemic disease, many studies have been conducted to find effective drugs to prevent COVID-19, because there are no specific drugs for the treatment of this disease. Most of these drugs with the antiviral potential effect toward COVID-19 are already used as the treatment of other infectious diseases. Some drugs that show the promising therapeutic potential in the initial clinical studies include remdesivir as an inhibitor of RNA-dependent RNA polymerase and favipiravir as an inhibitor of virus replication. Currently, remdesivir received the FDA authorizes to use as an experimental drug for emergency use in COVID-19 patients.","type":"Review","database":"PubMed","created":"2021-01-18"},{"id":493,"name":"Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19","author":"Moshe Rogosnitzky, Paul Okediji, Igor Koman ","doi":"10.1007\/s43440-020-00132-z","abstract":"Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-\u03baB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP\u2019s potential therapeutic importance as a drug of choice in managing COVID-19 cases.","type":"Review","database":"PubMed","created":"2021-01-17"},{"id":492,"name":"Repurposing Drugs for the Management of Patients with Confirmed Coronavirus Disease 2019 (COVID-19)","author":"Evellyn Claudia Wietzikoski Lovato, Lorena Neris Barboza, Samantha Wietzikoski, Amanda Nascimento Vasques de Souza, Pablo Alvarez Auth, Arquimedes Gasparotto Junior, Francislaine Aparecida dos Reis L\u00edvero","doi":"10.2174\/1381612826666200707121636","abstract":"Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed coronavirus disease 2019 (COVID-19) by the World Health Organization, is a newly emerging zoonotic agent that emerged in China in December 2019. No specific treatment for COVID-19 is currently available. Usual palliative treatment includes maintaining hydration and nutrition and controlling fever and cough. The clinical severity and extent of transmission need to be determined, and therapeutic options need to be developed and optimized.\r\n\r\nMethods: The present review discusses the recent repurposing of drugs for COVID-19 treatment.\r\nResults: Several compounds, including remdesivir, lopinavir, ritonavir, interferon-\u03b2, ribavirin, chloroquine\/ hydroxychloroquine, azithromycin, tocilizumab, and ivermectin, have emerged as promising alternatives. They block the virus from entering host cells, prevent viral replication, and attenuate exacerbation of the host's immune response.\r\nConclusion: Although some evidence indicates the positive actions of different classes of compounds for the treatment of COVID-19, few clinical assays have been established to definitively demonstrate their therapeutic value in humans. Multicenter clinical studies are urgently needed to validate and standardize therapeutic regimens that involve these agents. Although science has not yet presented us with a specific drug against COVID-19, the repurposing of drugs appears to be promising in our fight against this devastating disease.","type":"Review","database":"PubMed","created":"2021-01-17"},{"id":491,"name":"Therapeutic Targets and Computational Approaches on Drug Development for COVID-19","author":"Anusuya Shanmugam, Nisha Muralidharan, Devadasan Velmurugan, M. Michael Gromiha","doi":"10.2174\/1568026620666200710105507","abstract":"World Health Organization declared coronavirus disease (COVID-19) caused by SARS coronavirus-2 (SARS-CoV-2) as pandemic. Its outbreak started in China in Dec 2019 and rapidly spread all over the world. SARS-CoV-2 has infected more than 800,000 people and caused about 35,000 deaths so far, moreover, no approved drugs are available to treat COVID-19. Several investigations have been carried out to identify potent drugs for COVID-19 based on drug repurposing, potential novel compounds from ligand libraries, natural products, short peptides, and RNAseq analysis. This review is focused on three different aspects; (i) targets for drug design (ii) computational methods to identify lead compounds and (iii) drugs for COVID-19. It also covers the latest literature on various hit molecules proposed by computational methods and experimental techniques.","type":"Review","database":"PubMed","created":"2021-01-17"},{"id":490,"name":"Drug Repurposing and New Therapeutic Strategies for SARS-CoV-2 Disease Using a Novel Molecular Modeling-AI Hybrid Workflow","author":"Scott Bembenek","doi":"10.26434\/chemrxiv.12449081.v1","abstract":"The recent outbreak of the novel coronavirus (SARS-CoV-2) poses a significant challenge to the scientific and medical communities to find immediate treatments. The usual process of identifying viable molecules and transforming them into a safe and effective drug takes 10-15 years, with around 5 years of that time spent in preclinical research and development alone. The fastest strategy is to identify existing drugs or late-stage clinical molecules (originally intended for other therapeutic targets) that already have some level of efficacy. To this end, we tasked our novel molecular modeling-AI hybrid computational platform with finding potential inhibitors of the SARS-CoV-2 main protease (Mpro, 3CLpro). Over 13,000 FDA-approved drugs and clinical candidates (represented by just under 30,000 protomers) were examined. This effort resulted in the identification of several promising molecules. Moreover, it provided insight into key chemical motifs surely to be beneficial in the design of future inhibitors. Finally, it facilitated a unique perspective into other potentially therapeutic targets and pathways for SARS-CoV-2.","type":"Research","database":"ChemRxiv","created":"2021-01-17"},{"id":489,"name":"Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target","author":"Serdar Durdagi","doi":"10.26434\/chemrxiv.12442736.v1","abstract":"Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC\u2019s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM\/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.","type":"Research","database":"ChemRxiv","created":"2021-01-17"},{"id":488,"name":"Rationale Based Selection and Prioritization of Antiviral Drugs for COVID-19 Management","author":"Rakesh Joshi, Ashok P. Giri, Mahesh J. Kulkarni, Mahesh Gupta, Savita Verma, Dhruva Chaudhary, Narendra Deshmukh, Anita Chugh","doi":"10.26434\/chemrxiv.12429629.v1","abstract":"Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5\r\nmillion individuals with around 0.35 million deaths worldwide till May 2020 end. Several\r\nefforts are on in search of therapeutic interventions, but the preferred way is drug\r\nrepurposing due to the feasibility and urgency of the situation. To select and prioritize\r\napproved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs having\r\nproven safety profile in humans were subjected to virtual screening for binding to three\r\nselect targets namely human angiotensin-converting enzyme receptor-2 receptor-binding\r\ndomain (hACE-2) involved in virus entry, SARS-CoV-2 RNA dependent RNA polymerase\r\n(RdRp) responsible for viral RNA replication and SARS-CoV-2 main protease (MPro) causing\r\nproteolytic processing of viral polyprotein slab. Targeting multiple \u2018disease pathogenesis\r\nspecific proteins\u2019 within a close network of interaction or having dependent functionality can\r\nprovide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine and\r\nIndinavir were identified as candidate drugs of interest for COVID-19 based on a derived\r\ncombined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir and\r\nDaclatasvir and their approved marketed combination with Sofosbuvir emerged as leading\r\ncandidate drugs\/drug combinations for SARS-CoV-2. These candidates have the potential\r\nfor the antiviral activity for SARS-CoV-2 infection better than the investigational drug\r\nRemdesivir and other antiviral drugs\/drug combinations being evaluated. These\r\ndrugs\/combinations merit systematic fast track preclinical and clinical evaluation for COVID-\r\n19 management. The present work brings back attention to the potential usefulness of\r\napproved antiviral drugs\/drug combinations, commonly available with established safety\r\nprofile, currently not in focus for COVID-19. It provides a rationale based approach for the\r\nselection of drugs with potential antiviral activity against SARS-CoV-2 highlighting the\r\ndesired properties.","type":"Research","database":"ChemRxiv","created":"2021-01-17"},{"id":487,"name":"Structural insights into the binding modes of viral RNA-dependent RNA polymerases using a function-site interaction fingerprint method for RNA virus drug discovery","author":"Zheng Zhao, Phil Bourne","doi":"10.26434\/chemrxiv.12413360.v1","abstract":"The COVID-19 pandemic speaks to the need for drugs that are not only effective but also remain so given the mutation rate of COVID-19. To this end, we describe a strategy to design potential drugs that target RNA-dependent RNA polymerase (RDRP), a common conserved component of RNA viruses. We combine an RDRP structure dataset and all RDRP-ligand interaction fingerprints into an RDRP-targeted drug discovery procedure. In so doing we reveal the ligand-binding modes and RDRP structural characteristics. Specifically, four types of binding modes with corresponding binding pockets were determined, suggesting two major potential sub-pockets available for drug discovery. We screened a drug dataset of approximately 8,000 compounds against these binding pockets and presented the top ten small molecules as a starting point in further exploring the prevention of virus replication. In summary, the binding characteristics determined here help rationalize RDRP targeted drug discovery and provide insights into the specific binding mechanisms.","type":"Research","database":"ChemRxiv","created":"2021-01-17"},{"id":486,"name":"Simultaneous Inhibition of Entry and Replication of Novel Corona Virus by Grazoprevir: A Computational Drug Repurposing Study","author":"Santosh Kumar Behera, Nazmina Vhora, Darshan Contractor, Amit Shard, Dinesh Kumar, Kiran Kalia, Alok Jain","doi":"10.26434\/chemrxiv.12434174.v1","abstract":"It is evident from the on-going clinical studies (trials) for coronavirus disease 2019 (COVID-19) that treatment with a single drug is not likely to be sufficient. This, in turn, suggests that the drug acts via inhibition of multiple pathways likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for HCV, mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin Converting Enzyme 2 (ACE- 2)\/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent, RNA polymerase (RdRP). We believe that Grazoprevir either alone or given in combination could be effective therapeutics for treatment of COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibition of eukaryotic and viral proteins.","type":"Research","database":"ChemRxiv","created":"2021-01-17"},{"id":485,"name":"Bepridil is potent against SARS-CoV-2 In Vitro","author":"Erol C. Vatansever, Kai Yang, Kaci C. Kratch, Aleksandra Drelich, Chia-Chuan Cho, Drake M. Mellott, Shiqing Xu, Chien-Te K. Tseng, Wenshe Ray Liu","doi":"10.1101\/2020.05.23.112235","abstract":"Guided by a computational docking analysis, about 30 FDA\/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100 \u03bcM. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-2 entry into the human cell host and inhibiting MPro in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS-CoV-2 in Vero E6 cells completely at and dose-dependently below 5 \u03bcM and in A549 cells completely at and dose-dependently below 6.25 \u03bcM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.","type":"Research","database":"BioRxiv","created":"2021-01-17"},{"id":483,"name":"Drug Repurposing for Covid-19: Discovery of Potential Small-Molecule Inhibitors of Spike Protein-ACE2 Receptor Interaction Through Virtual Screening and Consensus Scoring","author":"Sachin Patil, Jeremy Hofer, Pedro J. Ballester, Elena Fattakhova, Juliette DiFlumeri, Autumn Campbell, Michael Oravic","doi":"10.26434\/chemrxiv.12482435.v1","abstract":"Objective\r\n\r\nThere is an increased interest in drug repurposing against Covid-19 (SARS-CoV-2) as its spread has significantly outpaced development of effective therapeutics. Our aim is to identify approved drugs that can inhibit the interaction of SARS-CoV-2 spike protein with human angiotensin-converting enzyme 2 (ACE2) that is critical for coronavirus infection.\r\n\r\nMethods\r\n\r\nThe published crystal structure of SARS-CoV-2 spike protein-ACE2 receptor interaction was first analyzed for druggable binding pockets. The binding interface was then probed by an integrated virtual screening protocol executed by a high-performance computer cluster, involving docking and consensus scoring using various machine-learning, empirical and knowledge-based scoring functions. The consensus-ranked lists of screened drugs were generated via \u2018rank-by-rank\u2019 and \u2018rank-by-number\u2019 schemes.\r\n\r\nFindings\r\n\r\nAlthough spike protein and ACE2 lacked druggable pockets in their unbound forms, they presented a well-defined pocket when bound together. Accordingly, we identified many drugs with high binding potential against this protein-protein interaction pocket. Importantly, several antivirals against two major (+)ssRNA viruses (HCV and HIV) constituted major group of our top hits, of which Atazanavir, Grazoprevir, Saquinavir, Simeprevir, Telaprevir and Tipranavir could be of most importance for immediate experimental\/clinical investigations. Additional notable hits included many anti-inflammatory\/antioxidant, antibiotic\/antifungal, and other relevant compounds with proven activity against respiratory diseases, further emphasizing robustness of our current study. Notably, we also discovered Maraviroc, the only FDA-approved drug capable of targeting virus-host interaction and blocking HIV entry.\r\n\r\nConclusion\r\n\r\nOur newly identified compounds warrant further experimental investigation against SARS-CoV-2 spike-ACE2 interaction, which if proven effective may present much-needed immediate clinical potential against Covid-19.","type":"Research","database":"ChemRxiv","created":"2021-01-17"},{"id":482,"name":"In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing","author":"Yogesh Kumara, Harvijay Singh, Chirag N.Patel","doi":"10.1016\/j.jiph.2020.06.016","abstract":"Background\r\nThe rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded \u03b1-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding.\r\n\r\nMethods\r\nFor the study, we have targeted the SARS-CoV-2 Mpro for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 Mpro active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries.\r\n\r\nResults\r\nThe phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir\u2013Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 Mpro protein.\r\n\r\nConclusions\r\nIn the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir\u2013Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.","type":"Research","database":"PubMed","created":"2021-01-17"},{"id":481,"name":"Combined drug repurposing and virtual screening strategies with molecular dynamics simulation identified potent inhibitors for SARS-CoV-2 main protease (3CLpro)","author":"Abbas Khan, Syed Shujait Ali, Muhammad Tahir Khan, Shoaib Saleem, Arif Ali, Muhammad Suleman, Zainib Babar, Athar Shafiq, Mazhar Khan, Dong-Qing Wei","doi":"10.1080\/07391102.2020.1779128","abstract":"The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle.","type":"Research","database":"PubMed","created":"2021-01-17"},{"id":480,"name":"Therapeutic drugs for SARS-CoV-2 treatment: Current state and perspective","author":"Joshua Adedeji Bolarin, Mercy Adaramodu Oluwatoyosi, Joshua Iseoluwa Orege, Emmanuel Ayodeji Ayeni, Yusuf Ajibola Ibrahim, Sherif Babatunde Adeyemi, Bashir Bolaji Tiamiyu, Lanre Anthony Gbadegesin, Toluwanimi Oluwadara Akinyemi, Chuks Kenneth Odoh, Happiness Ijeoma Umeobi, Adenike Bernice-Eloise Adeoye,","doi":"10.1016\/j.intimp.2020.107228","abstract":"The disease caused by viral pneumonia called severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) declared by the World Health Organization is a global pandemic that the world has witnessed since the last Ebola epidemic, SARS and MERS viruses. Many chemical compounds with antiviral activity are currently undergoing clinical investigation in order to find treatments for SARS-CoV-2 infected patients. On-going drug-drug interaction examinations on new, existing, and repurposed antiviral drugs are yet to provide adequate safety, toxicological, and effective monitoring protocols. This review presents an overview of direct and indirect antiviral drugs, antibiotics, and immune-stimulants used in the management of SARS-CoV-2. It also seeks to outline the recent development of drugs with anti-coronavirus effects; their mono and combination therapy in managing the disease vis-\u00e0-vis their biological sources and chemistry. Co-administration of these drugs and their interactions were discussed to provide significant insight into how adequate monitoring of patients towards effective health management could be achieved.","type":"Review","database":"PubMed","created":"2021-01-11"},{"id":479,"name":"Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture","author":"Khushboo Bafna, Kris White, Balasubramanian Harish, Romel Rosales,  Theresa A. Ramelot, Thomas B. Acton, Elena Moreno, Thomas Kehrer, Lisa Miorin,  Catherine A. Royer,  Adolfo Garc\u00eda-Sastre, Robert M. Krug,  Gaetano T. Montelione","doi":"10.1101\/2020.12.13.422511","abstract":"Effective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 Mpro and HCV NS3\/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mpro binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 Mpro protease activity, while four dock well into the PLpro substrate binding cleft and inhibit PLpro protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and\/or human cells, demonstrating that HCV drugs that inhibit Mpro, or both Mpro and PLpro, suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold.\r\n\r\nHighlights\r\nSeveral HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mpro and PLpro.\r\nSeven HCV drugs inhibit Mpro enzyme activity, four HCV drugs inhibit PLpro.\r\nSeven HCV drugs inhibit SARS-CoV-2 replication in Vero and\/or human cells.\r\nHCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2.\r\n\r\neTOC blurb Bafna, White and colleagues report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 Mpro and\/or PLpro proteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold.","type":"Research","database":"BioRxiv","created":"2021-01-11"},{"id":478,"name":"Leaving no stone unturned: Allosteric targeting of SARS-CoV-2 spike protein at putative druggable sites disrupts human angiotensin-converting enzyme interactions at the receptor binding domain","author":"Fisayo A. Olotu, Kehinde F. Omolabi, Mahmoud E. S. Soliman","doi":"10.1016\/j.imu.2020.100451","abstract":"The systematic entry of SARS-CoV-2 into host cells, as mediated by its Spike (S) protein, is highly essential for pathogenicity in humans. Hence, targeting the viral entry mechanisms remains a major strategy for COVID-19 treatment. Although recent efforts have focused on the direct inhibition of S-protein receptor-binding domain (RBD) interactions with human angiotensin-converting enzyme 2 (hACE2), allosteric targeting remains an unexplored possibility. Therefore, in this study, for the first time, we employed an integrative meta-analytical approach to investigate the allosteric inhibitory mechanisms of SARS-CoV-2 S-protein and its association with hACE2. Findings revealed two druggable sites (Sites 1 and 2) located at the N-terminal domain (NTD) and S2 regions of the protein. Two high-affinity binders; ZINC3939013 (Fosaprepitant \u2013 Site 1) and ZINC27990463 (Lomitapide \u2013 Site 2) were discovered via site-directed high-throughput screening against a library of ~1500 FDA approved drugs. Interestingly, we observed that allosteric binding of both compounds perturbed the prefusion S-protein conformations, which in turn, resulted in unprecedented hACE2 displacement from the RBD. Estimated \u0394Gbinds for both compounds were highly favorable due to high-affinity interactions at the target sites. In addition, Site 1 residues; R190, H207, K206 and K187, I101, R102, I119, F192, L226, V126 and W104 were identified for their crucial involvement in the binding and stability of ZINC3939013. Likewise, energy contributions of Q957, N953, Q954, L303, Y313, Q314, L858, V952, N953, and A956 corroborated their importance to ZINC27990463 binding at the predicted Site 2. We believe these findings would pave way for the structure-based discovery of allosteric SARS-CoV-2 S-protein inhibitors for COVID-19 treatment.","type":"Research","database":"PubMed","created":"2021-01-11"},{"id":477,"name":"Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs","author":"Zhe Li, Xin Li, Yi-You Huang, Yaoxing Wu, Runduo Liua, Lingli Zhou, Yuxi Lin, Deyan Wu, Lei Zhang, Hao Liu, Ximing Xu, Kunqian Yu, Yuxia Zhang, Jun Cui, Chang-Guo Zhan, Xin Wang, Hai-Bin Luo","doi":"10.1073\/pnas.2010470117","abstract":"The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis.\r\nThere is no therapeutic treatment specific for COVID-19. It is highly\r\ndesirable to identify potential antiviral agents against SARS-CoV-2\r\nfrom existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19,\r\nusually starts from a virtual screening of existing drugs, followed\r\nby experimental validation, but the actual hit rate is generally\r\nrather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy\r\nperturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2\r\nmain protease (Mpro). The accurate FEP-ABFE predictions were\r\nbased on the use of a restraint energy distribution (RED) function,\r\nmaking the practical FEP-ABFE\u2212based virtual screening of the\r\nexisting drug library possible. As a result, out of 25 drugs predicted,\r\n15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The\r\nmost potent one is dipyridamole (inhibitory constant Ki = 0.04\r\n\u03bcM) which has shown promising therapeutic effects in subsequently\r\nconducted clinical studies for treatment of patients with COVID-19.\r\nAdditionally, hydroxychloroquine (Ki = 0.36 \u03bcM) and chloroquine\r\n(Ki = 0.56 \u03bcM) were also found to potently inhibit SARS-CoV-2 Mpro.\r\nWe anticipate that the FEP-ABFE prediction-based virtual screening\r\napproach will be useful in many other drug repurposing or\r\ndiscovery efforts.","type":"Research","database":"PubMed","created":"2021-01-11"},{"id":476,"name":"Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.","author":"Gagandeep Singh, vishal srivastava, Ritpratik Mishra, Gaurav Goel, Tapan Chaudhuri","doi":"10.26434\/chemrxiv.13032578.v1","abstract":"In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people,\r\ncausing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug\r\ndesign pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around\r\nten years in general from identifying a clinical candidate to get the approvals for actual applications. An\r\neffective way to cut short drug design pipeline in such emergency cases could be the repurposing of already\r\napproved drugs against novel targets. Here in this work, we explored the structure-based drug screening\r\napproach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA\r\napproved commercially available drugs. The site-specific and blind docking studies, in combination, suggest\r\nthree potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and\r\nNaldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy\r\ncalculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor\r\ncandidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs\r\nbefore utilizing them for the therapeutic management of SARS-CoV2 infection.","type":"Research","database":"ChemRxiv","created":"2021-01-11"},{"id":475,"name":"Spontaneous Binding of Potential COVID-19 Drugs to Human Serine Protease TMPRSS2","author":"Zhu Haixia, Du Wenhao, Song Menghua, Liu Qing, Herrmann Andreas, Huang Qiang","doi":"10.26434\/chemrxiv.13049663.v1","abstract":"Effective treatment or vaccine is not yet available for combating SARS coronavirus 2 (SARSCoV-2) that caused the COVID-19 pandemic. Recent studies showed that two drugs,\r\nCamostat and Nafamostat, might be repurposed to treat COVID-19 by inhibiting human\r\nTMPRSS2 required for proteolytic activation of viral spike (S) glycoprotein. However, their\r\nmolecular mechanisms of pharmacological action remain unclear. Here, we perform\r\nmolecular dynamics simulations to investigate their native binding sites on TMPRSS2. We\r\nrevealed that both drugs could spontaneously and stably bind to the TMPRSS2 catalytic\r\ncenter, and thereby inhibit its proteolytic processing of the S protein. Also, we found that\r\nNafamostat is more specific than Camostat for binding to the catalytic center, consistent with\r\nreported observation that Nafamostat blocks the SARS-CoV-2 infection at a lower\r\nconcentration. Thus, this study provides mechanistic insights into the Camostat and\r\nNafamostat inhibition of the SARS-CoV-2 infection, and offers useful information for\r\nCOVID-19 drug development. ","type":"Research","database":"ChemRxiv","created":"2021-01-11"},{"id":474,"name":"Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19","author":"Wanchao Yin, Xiaodong Luan, Zhihai Li, Leike Zhang, Ziwei Zhou, Minqi Gao, Xiaoxi Wang, Fulai Zhou, Jingjing Shi, Erli You, Mingliang Liu, Qingxia Wang, Qingxing Wang, Yi Jiang, Hualiang Jiang, Gengfu Xiao, Xuekui Yu, Shuyang Zhang, H. Eric Xu","doi":"10.1101\/2020.10.06.328336","abstract":"The COVID-19 pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) through blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for COVID-19. The 2.6 \u00c5 cryo-EM structure of the viral RdRp bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp catalytic active site, therefore inhibiting the viral RNA replication. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp and a rationale for repurposing suramin for treating COVID-19.","type":"Research","database":"BioRxiv","created":"2021-01-11"},{"id":473,"name":"Cardiovascular drugs and COVID-19 clinical outcomes: a living systematic review and meta-analysis","author":"Innocent G Asiimwe, Sudeep Pushpakom, Richard M Turner, Ruwanthi Kolamunnage-Dona, Andrea Jorgensen, Munir Pirmohamed","doi":"10.1101\/2020.10.07.20208918","abstract":"OBJECTIVE To continually evaluate the rapidly evolving evidence base on the role of cardiovascular drugs in COVID-19 clinical outcomes (susceptibility to infection, hospitalization, hospitalization length, disease severity, and all-cause mortality).\r\n\r\nDESIGN Living systematic review and meta-analysis.\r\n\r\nDATA SOURCES Eligible publications identified from >500 databases indexed through 31st July 2020 and additional studies from reference lists, with planned continual surveillance for at least two years.\r\n\r\nSTUDY SELECTION Observational and interventional studies that report on the association between cardiovascular drugs and COVID-19 clinical outcomes.\r\n\r\nDATA EXTRACTION Single-reviewer extraction and quality evaluation (using ROBINS-I), with half the records independently extracted and evaluated by a second reviewer.\r\n\r\nRESULTS Of 23,427 titles screened, 175 studies were included in the quantitative synthesis. The most reported drug classes were angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) with ACEI\/ARB exposure being associated with higher odds of testing positive for COVID-19 (pooled unadjusted OR 1.15, 95% CI 1.02 to 1.30). Among patients with COVID-19, unadjusted estimates showed that ACEI\/ARB exposure was associated with being hospitalized (OR 2.25, 1.70 to 2.98) and having severe disease (OR 1.50, 1.27 to 1.77) but not with the length of hospitalization (mean difference \u22120.45, \u22121.33 to 0.43 days) or all-cause mortality (OR 1.25, CI 0.98 to 1.58). However, after adjustment, ACEI\/ARB exposure was not associated with testing positive for COVID-19 (pooled adjusted OR 1.01, 0.93 to 1.10), being hospitalized (OR 1.16, 0.80 to 1.68), having severe disease (1.04, 0.76 to 1.42), or all-cause mortality (0.86, 0.64 to 1.15). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI\/ARB exposure was not associated with being hospitalized (OR 0.84, 0.58 to 1.22), disease severity (OR 0.88, 0.68 to 1.14) or all-cause mortality (OR 0.77, 0.54 to 1.12) while it decreased the length of hospitalization (mean difference \u22120.71, \u22121.11 to \u22120.30 days). After adjusting for relevant covariates, other cardiovascular drug classes were mostly not found to be associated with poor COVID-19 clinical outcomes. However, the validity of these findings is limited by a high level of heterogeneity in terms of effect sizes and a serious risk of bias, mainly due to confounding in the included studies.\r\n\r\nCONCLUSION Our comprehensive review shows that ACEI\/ARB exposure is associated with COVID-19 outcomes such as susceptibility to infection, severity, and hospitalization in unadjusted analyses. However, after adjusting for potential confounding factors, this association is not evident. Patients on cardiovascular drugs should continue taking their medications as currently recommended. Higher quality evidence in the form of randomized controlled trials will be needed to determine any adverse or beneficial effects of cardiovascular drugs.","type":"Review","database":"MedRxiv","created":"2021-01-11"},{"id":472,"name":"A pocket guide on how to structure SARS-CoV-2 drugs and therapies","author":" Dene R. Littler, Bruce J. MacLachlan, Gabrielle M. Watson, Julian P. Vivian, Benjamin S. Gully ","doi":"10.1042\/BST20200396","abstract":"The race to identify a successful treatment for COVID19 will be defined by fundamental research into the replication cycle of the SARS-CoV-2 virus. This has identified five distinct stages from which numerous vaccination and clinical trials have emerged alongside an innumerable number of drug discovery studies currently in development for disease intervention. Informing every step of the viral replication cycle has been an unprecedented \u2018call-to-arms' by the global structural biology community. Of the 20 main SARS-CoV-2 proteins, 13 have been resolved structurally for SARS-CoV-2 with most having a related SARS-CoV and MERS-CoV structural homologue totalling some 300 structures currently available in public repositories. Herein, we review the contribution of structural studies to our understanding of the virus and their role in structure-based development of therapeutics.","type":"Review","database":"PubMed","created":"2021-01-04"},{"id":471,"name":"Recent Advances in Pathophysiology, Drug Development and Future Perspectives of SARS-CoV-2","author":"Desh Deepak Singh, Ihn Han, Eun-Ha Choi, Dharmendra K. Yadav","doi":"10.3389\/fcell.2020.580202","abstract":"The coronavirus (SARS-CoV-2) pandemic is a rapidly transmitting and highly pathogenic disease. The spike protein of SARS-CoV-2 binds to the surface of angiotensin-converting enzyme-2 (ACE2) receptors along the upper respiratory tract and intestinal epithelial cells. SARS-CoV-2 patients develop acute respiratory distress, lymphocytic myocarditis, disseminated intravascular coagulation, lymphocytic infiltration, and other serious complications. A SARS-CoV-2 diagnosis is conducted using quantitative reverse-transcription PCR and computed tomography (CT) imaging. In addition, IgM or IgG antibodies are used to identify acute and convalescent illness. Recent clinical data have been generated by health workers and researchers and have shown that there is an urgent requirement in the effective clinical and treatment of patients, as well as other developments for dealing with SARS-CoV-2 infection. A broad spectrum of clinical trials of different vaccines and drug treatment has been evaluated for use against SARS-CoV-2. This review includes the emergence of SARS-CoV-2 pneumonia as a way to recognize and eliminate any barriers that affect rapid patient care and public health management against the SARS-CoV-2 epidemic based on the natural history of the disease, its transmission, pathogenesis, immune response, epidemiology, diagnosis, clinical presentation, possible treatment, drug and vaccine development, prevention, and future perspective.","type":"Review","database":"PubMed","created":"2021-01-04"},{"id":470,"name":"Safety of hydroxychloroquine for treatment or prevention of SARS\u2010CoV\u20102 infection: A rapid systematic review and meta\u2010analysis of randomized clinical trials","author":"Alberto Enrico Maraolo,  Adriano Grossi","doi":"10.1002\/iid3.374","abstract":"Introduction\r\nHydroxycloroquine (HCQ) has been extensively studied for treatment and prevention of coronavirus diseases 2019 (COVID\u201019) from the start of the pandemic. Conflicting evidence about its usefulness has begun to accrue.\r\n\r\nMethods\r\nIn the face of controversial results about clinical efficacy of HCQ, we performed a rapid systematic review to assess its safety in the framework of COVID\u201019 randomized clinical trials.\r\n\r\nResults\r\nFive studies investigating 2291 subjects were included. The use of HCQ was associated with higher risk of adverse event compared with placebo or standard of care: odds ratio 4.57, 95% confidence interval 2.14\u20139.45.\r\n\r\nConclusion\r\nSafety profile of HCQ appears to be unsatisfactory when used to treat or prevent COVID\u201019, especially in the light of unproved clinical benefit.","type":"Review","database":"PubMed","created":"2021-01-04"},{"id":469,"name":"SARS-CoV-2 Mpro inhibitors: identification of anti-SARS-CoV-2 Mpro compounds from FDA approved drugs","author":"Shiv Bharadwaj, Esam Ibraheem Azhar, Mohammad Amjad Kamal, Leena Hussein Bajrai, Amit Dubey, Kanupriya Jha, Umesh Yadava, Sang Gu Kang, Vivek Dhar Dwivedi","doi":"10.1080\/07391102.2020.1842807","abstract":"Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 Mpro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >\u22127\u2009kcal\/mol. The top 10 screened potential compounds against SARS-CoV-2 Mpro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100\u2009ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428 (\u221210.5\u2009kcal\/mol), Teniposide (\u22129.8\u2009kcal\/mol), VS-5584 (\u22129.4\u2009kcal\/mol), and Setileuton (\u22128.5\u2009kcal\/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2021-01-04"},{"id":468,"name":"Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies","author":"Ortega J.T. , Zambrano J.L. , Jastrzebska B. , Liprandi F. , Rangel H.R. , Pujol F.H.","doi":"10.1159\/000512141","abstract":"Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease CO\u00adVID-19 has strongly encouraged the search for antiviral compounds. Most of the evaluated drugs against SARS-CoV-2 derive from drug repurposing of Food and Drug Administration-approved molecules. These drugs have as target three major processes: (1) early stages of virus-cell interaction, (2) viral proteases, and (3) the viral RNA-dependent RNA polymerase. \r\n\r\nSummary: This review focused on the basic principles of virology and pharmacology to understand the importance of early stages of virus-cell interaction as therapeutic targets and other main processes vital for SARS-CoV-2 replication. Furthermore, we focused on describing the main targets associated with SARS-CoV-2 antiviral therapy and the rationale of drug combinations for efficiently suppressing viral replication. \r\n\r\nKey Messages: We hypothesized that blocking of both entry mechanisms could allow a more effective antiviral effect compared to the partial results obtained with chloroquine or its derivatives alone. This approach, already used to achieve an antiviral effect higher than that offered by every single drug administered separately, has been successfully applied in several viral infections such as HIV and HCV. This review will contribute to expanding the perception of the possible therapeutic targets in SARS-CoV-2 infection and highlight the benefits of using combination therapies.","type":"Review","database":"PubMed","created":"2021-01-04"},{"id":467,"name":"The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies","author":"Anastassios C. Papageorgiou, Imran Mohsin","doi":"10.3390\/cells9112343","abstract":"Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease (COVID-19) pandemic, has so far resulted in more than 1.1 M deaths and 40 M cases worldwide with no confirmed remedy yet available. Since the first outbreak in Wuhan, China in December 2019, researchers across the globe have been in a race to develop therapies and vaccines against the disease. SARS-CoV-2, similar to other previously identified Coronaviridae family members, encodes several structural proteins, such as spike, envelope, membrane, and nucleocapsid, that are responsible for host penetration, binding, recycling, and pathogenesis. Structural biology has been a key player in understanding the viral infection mechanism and in developing intervention strategies against the new coronavirus. The spike glycoprotein has drawn considerable attention as a means to block viral entry owing to its interactions with the human angiotensin-converting enzyme 2 (ACE2), which acts as a receptor. Here, we review the current knowledge of SARS-CoV-2 and its interactions with ACE2 and antibodies. Structural information of SARS-CoV-2 spike glycoprotein and its complexes with ACE2 and antibodies can provide key input for the development of therapies and vaccines against the new coronavirus.","type":"Review","database":"PubMed","created":"2021-01-04"},{"id":466,"name":"A multi-stage virtual screening of FDA-approved drugs reveals potential inhibitors of SARS-CoV-2 main protease","author":"Yasmine M. Mandour, Darius P. Zlotos, M. Alaraby Salem","doi":"10.1080\/07391102.2020.1837680","abstract":"Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Repurposing of approved pharmaceutical drugs for COVID-19 treatment represents an attractive approach to quickly identify promising drug candidates. SARS-CoV-2 main protease (Mpro) is responsible for the maturation of viral functional proteins making it a key antiviral target. Based on the recently revealed crystal structures of SARS-CoV-2 Mpro, we herein describe a multi-stage virtual screening protocol including pharmacophore screening, molecular docking and protein-ligand interaction fingerprints (PLIF) post-docking filtration for efficient enrichment of potent SARS-CoV-2 Mpro inhibitors. Potential hits, along with a cocrystallized control were further studied via molecular dynamics. A 150-ns production trajectory was followed by RMSD, free energy calculation, and H-bond analysis for each compound. The applied virtual screening protocol led to identification of five FDA-approved drugs with promising binding modes to key subsites of the substrate-binding pocket of SARS-CoV-2 Mpro. The identified compounds belong to different pharmaceutical classes, including several protease inhibitors, antineoplastic agents and a natural flavonoid. The drug candidates discovered in this study present a potential extension of the recently reported SARS-CoV-2 Mpro inhibitors that have been identified using other virtual screening protocols and may be repurposed for COVID-19 treatment.","type":"Research","database":"PubMed","created":"2020-12-15"},{"id":465,"name":"Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine 2 and itraconazole effectively impairs SARS-CoV-2 infection in vitro. ","author":"Sebastian Schloer, Linda Brunotte, Angeles Mecate-Zambrano, Shuyu Zheng, Jing Tang, Stephan Ludwig, Ursula Rescher","doi":"10.1101\/2020.10.16.342410","abstract":"The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently calls for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here we investigated the therapeutic potential of targeting the host- SARS-CoV-2 interface via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs. We tested the antiviral potential of repurposing the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with remdesivir, an inhibitor of viral RNA polymerase. Drug treatments were well-tolerated and potent impaired viral replication was observed with all drug treatments. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects in commonly used reference models for drug interaction. Itraconazole-Remdesivir and Fluoxetine-Remdesivir combinations are promising therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.","type":"Research","database":"BioRxiv","created":"2020-12-15"},{"id":464,"name":"Repurposing Existing Drugs for the Treatment of COVID-19","author":"Hugo Farne , Kartik Kumar , Andrew I. Ritchie , Lydia J. Finney , Sebastian L. Johnston ,  Aran Singanayagam","doi":"10.1513\/AnnalsATS.202005-566FR  ","abstract":"The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist; thus, development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and antiinflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date, only dexamethasone and remdesivir have been shown to be effective, but several other promising candidates are in trials.","type":"Review","database":"PubMed","created":"2020-12-15"},{"id":463,"name":"High-Throughput Screening for Drugs That Inhibit Papain-Like Protease in SARS-CoV-2","author":"Emery Smith, Meredith E. Davis-Gardner, Ruben D. Garcia-Ordonez, Tu-Trinh Nguyen, Mitchell Hull, Emily Chen, Pierre Baillargeon, Louis Scampavia, Timothy Strutzenberg, Patrick R. Griffin, Michael Farzan, Timothy P. Spicer","doi":"10.1177\/2472555220963667","abstract":"The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 has triggered an ongoing global pandemic whereby infection may result in a lethal severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, millions of confirmed cases and hundreds of thousands of deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. The purported development of a vaccine could require at least 1\u20134 years, while the typical timeline from hit finding to drug registration of an antiviral is >10 years. Thus, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we developed and initiated a high-throughput cell-based screen that incorporates the essential viral papain-like protease (PLpro) and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or US Food and Drug Administration (FDA)-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Here, we report the identification of four clinically relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral PLpro.","type":"Research","database":"PubMed","created":"2020-12-15"},{"id":462,"name":"RNA-dependent RNA polymerase: Structure, mechanism, and drug discovery for COVID-19","author":"Yi Jiang, Wanchao Yin, H. Eric Xu","doi":"10.1016\/j.bbrc.2020.08.116","abstract":"Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global pandemic. Although great efforts have been made to develop effective therapeutic interventions, only the nucleotide analog remdesivir was approved for emergency use against COVID-19. Remdesivir targets the RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral RNA replication and a promising drug target for COVID-19. Recently, several structures of RdRp in complex with substrate RNA and remdesivir were reported, providing insights into the mechanisms of RNA recognition by RdRp. These structures also reveal the mechanism of RdRp inhibition by nucleotide inhibitors and offer a molecular template for the development of RdRp-targeting drugs. This review discusses the recognition mechanism of RNA and nucleotide inhibitor by RdRp, and its implication in drug discovery.","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":461,"name":"Coronavirus Disease (COVID-19): Current Status and Prospects for Drug and Vaccine Development","author":"Kevin Ita","doi":"10.1016\/j.arcmed.2020.09.010","abstract":"The Coronavirus disease 2019 (COVID-19) pandemic has spread to almost all nooks and corners of the world. There are numerous potential approaches to pharmacologically fight COVID-19: small-molecule drugs, interferon therapies, vaccines, oligonucleotides, peptides, and monoclonal antibodies. Medications are being developed to target the spike, membrane, nucleocapsid or envelope proteins. The spike protein is also a critical target for vaccine development. Immunoinformatic approaches are being used for the identification of B cell and cytotoxic T lymphocyte (CTL) epitopes in the SARS-CoV-2 spike protein. Different vaccine vectors are also being developed. Chemical and physical methods such as formaldehyde, UV light or \u03b2-propiolactone are being deployed for the preparation of inactivated virus vaccine. Currently, there are many vaccines undergoing clinical trials. Even though mRNA and DNA vaccines are being designed and moved into clinical trials, these types of vaccines are yet to be approved by regulatory bodies for human use. This review focuses on the drugs and vaccines being developed against the COVID-19.","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":460,"name":"Important Pharmacogenetic Information for Drugs Prescribed During the SARS\u2010CoV\u20102 Infection (COVID\u201019)","author":"Pablo Zubiaur  Dora Koller  Miriam Saiz\u2010Rodr\u00edguez  Marcos Navares\u2010G\u00f3mez  Francisco Abad\u2010Santos","doi":"10.1111\/cts.12866","abstract":"In December 2019, the severe acute respiratory syndrome virus\u20102 pandemic began, causing the coronavirus disease 2019. A vast variety of drugs is being used off\u2010label as potential therapies. Many of the repurposed drugs have clinical pharmacogenetic guidelines available with therapeutic recommendations when prescribed as indicated on the drug label. The aim of this review is to provide a comprehensive summary of pharmacogenetic biomarkers available for these drugs, which may help to prescribe them more safely.","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":459,"name":"Lopinavir-Ritonavir in SARS-CoV-2 Infection and Drug-Drug Interactions with Cardioactive Medications","author":"Shubham Agarwal, Sanjeev Kumar Agarwal","doi":"10.1007\/s10557-020-07070-1","abstract":"Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care.","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":458,"name":"Virtual screening of approved clinic drugs with main protease (3CLpro) reveals potential inhibitory effects on SARS-CoV-2","author":"Qiang Wang, Ying Zhao, Xiaojia Chen, An Hong","doi":"10.1080\/07391102.2020.1817786","abstract":"3CLpro is the main protease of the novel coronavirus (SARS-CoV-2) responsible for their intracellular duplication. Based on virtual screening technology and molecular dynamics simulation, we found 23 approved clinical drugs such as Viomycin, Capastat, Carfilzomib and Saquinavir, which showed high affinity with the 3CLpro active sites. These findings showed that there were potential drugs that inhibit SARS-Cov-2's 3CLpro in the current clinical drug library, and these drugs can be further tested or chemically modified for the treatment of COVID-19.","type":"Research","database":"PubMed","created":"2020-12-14"},{"id":457,"name":"Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach","author":"Md. Sorwer Alam Parveza, Md. Adnan Karim, Mahmudul Hasan, Jomana Jaman, Ziaul Karim, Tohura Tahsin, Md. Nazmul Hasan, Mohammad Jakir Hosen","doi":"10.1016\/j.ijbiomac.2020.09.098","abstract":"The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5\u2032-triphosphate-5\u2032-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.","type":"Research","database":"PubMed","created":"2020-12-14"},{"id":456,"name":"Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation","author":"Mathieu Gendrot, Julien Andreani, Manon Boxberger, Priscilla Jardot, Isabelle Fonta, Marion Le Bideau, Isabelle Duflot, Joel Mosnier, Clara Rolland, Herv\u00e9 Bogreau, S\u00e9bastien Hutter, Bernard La Scola, BrunoPradines","doi":"10.1016\/j.tmaid.2020.101873","abstract":"In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs. We investigated the in vitro antiviral activity against SARS-CoV-2 of several antimalarial drugs. Chloroquine (EC50 = 2.1 \u03bcM and EC90 = 3.8 \u03bcM), hydroxychloroquine (EC50 = 1.5 \u03bcM and EC90 = 3.0 \u03bcM), ferroquine (EC50 = 1.5 \u03bcM and EC90 = 2.4 \u03bcM), desethylamodiaquine (EC50 = 0.52 \u03bcM and EC90 = 1.9 \u03bcM), mefloquine (EC50 = 1.8 \u03bcM and EC90 = 8.1 \u03bcM), pyronaridine (EC50 = 0.72 \u03bcM and EC90 = 0.75 \u03bcM) and quinine (EC50 = 10.7 \u03bcM and EC90 = 38.8 \u03bcM) showed in vitro antiviral effective activity with IC50 and IC90 compatible with drug oral uptake at doses commonly administered in malaria treatment. The ratio Clung\/EC90 ranged from 5 to 59. Lumefantrine, piperaquine and dihydroartemisinin had IC50 and IC90 too high to be compatible with expected plasma concentrations (ratio Cmax\/EC90 < 0.05). Based on our results, we would expect that countries which commonly use artesunate-amodiaquine or artesunate-mefloquine report fewer cases and deaths than those using artemether-lumefantrine or dihydroartemisinin-piperaquine. It could be necessary now to compare the antimalarial use and the dynamics of COVID-19 country by country to confirm this hypothesis.","type":"Research","database":"PubMed","created":"2020-12-14"},{"id":455,"name":"Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19","author":"Faheem, Banoth Karan Kumar, Kondapalli Venkata Gowri Chandra Sekhar, Selvaraj Kunjiappan, Joazaizulfazli Jamalis, Rafael Bala\u00f1a-Fouce, Babu L. Tekwani, Murugesan Sankaranarayanan","doi":"10.1016\/j.bioorg.2020.104269","abstract":"COVID-19 caused by the novel SARS-CoV-2 has been declared a pandemic by the WHO is causing havoc across the entire world. As of May end, about 6 million people have been affected, and 367 166 have died from COVID-19. Recent studies suggest that the SARS-CoV-2 genome shares about 80% similarity with the SARS-CoV-1 while their protein RNA dependent RNA polymerase (RdRp) shares 96% sequence similarity. Remdesivir, an RdRp inhibitor, exhibited potent activity against SARS-CoV-2 in vitro. 3-Chymotrypsin like protease (also known as Mpro) and papain-like protease, have emerged as the potential therapeutic targets for drug discovery against coronaviruses owing to their crucial role in viral entry and host-cell invasion. Crystal structures of therapeutically important SARS-CoV-2 target proteins, namely, RdRp, Mpro, endoribonuclease Nsp15\/NendoU and receptor binding domain of CoV-2 spike protein has been resolved, which have facilitated the structure-based design and discovery of new inhibitors. Furthermore, studies have indicated that the spike proteins of SARS-CoV-2 use the Angiotensin Converting Enzyme-2 (ACE-2) receptor for its attachment similar to SARS-CoV-1, which is followed by priming of spike protein by Transmembrane protease serine 2 (TMPRSS2) which can be targeted by a proven inhibitor of TMPRSS2, camostat. The current treatment strategy includes repurposing of existing drugs that were found to be effective against other RNA viruses like SARS, MERS, and Ebola. This review presents a critical analysis of druggable targets of SARS CoV-2, new drug discovery, development, and treatment opportunities for COVID-19.","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":454,"name":"Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2 in vitro","author":"Nir Drayman, Krysten A. Jones, Saara-Anne Azizi, Heather M. Froggatt, Kemin Tan, Natalia Ivanovna Maltseva, Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S. Kathayat, Mason R. Firpo, Vincent Mastrodomenico, Emily A. Bruce, Madaline M. Schmidt, Robert Jedrzejczak, Miguel \u00c1. Mu\u00f1oz-Al\u00eda, Brooke Schuster, Vishnu Nair, Jason W. Botten, Christopher B. Brooke, Susan C. Baker, Bryan C. Mounce, Nicholas S. Heaton, Bryan C. Dickinson, Andrzej Jaochimiak, Glenn Randall, Sava\u015f Tay","doi":"10.1101\/2020.08.31.274639","abstract":"There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.","type":"Research","database":"BioRxiv","created":"2020-12-14"},{"id":453,"name":"Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)","author":"Konstantinos Kalamatianos","doi":"10.26434\/chemrxiv.12857678.v1","abstract":"In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the corresponding binding affinities of seventeen such antiretroviral compounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, small charge separation, low electrophilicity, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and lopinavir showed excellent results \u2013 binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.","type":"Research","database":"ChemRxiv","created":"2020-12-14"},{"id":452,"name":"Biomedical application, drug delivery and metabolic pathway of antiviral nanotherapeutics for combating viral pandemic: A review","author":"Santanu Mukherjee, Payal Mazumder, Madhvi Joshi, Chaitanya Joshi, Sameer V. Dalvid, Manish Kumar","doi":"10.1016\/j.envres.2020.110119","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a neoteric virus belonging to the beta coronavirus class has created a global health concern, responsible for an outbreak of severe acute respiratory illness, the COVID-19 pandemic. Infected hosts exhibit diverse clinical features, ranging from asymptomatic to severe symptoms in their genital organs, respiratory, digestive, and circulatory systems. Considering the high transmissibility (R0: \u22646.0) compared to Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, the quest for the clinical development of suitable antiviral nanotherapeutics (NTPs) is incessant. We are presenting a systematic review of the literature published between 2003 and 2020 to validate the hypothesis that the pharmacokinetics, collateral acute\/chronic side effects of nano drugs and spike proteins arrangement of coronaviruses can revolutionize the therapeutic approach to cure COVID-19. Our aim is also to critically assess the slow release kinetics and specific target site chemical synthesis influenced competence of NTPs and nanotoxicity based antiviral actions, which are commonly exploited in the synthesis of modulated nanomedicines. The pathogenesis of novel virulent pathogens at the cellular and molecular levels are also considered, which is of utmost importance to characterize the emerging nano-drug agents as diagnostics or therapeutics or viral entry inhibitors. Such types of approaches trigger the scientists and policymakers in the development of a conceptual framework of nano-biotechnology by linking nanoscience and virology to present a smart molecular diagnosis\/treatment for pandemic viral infections.","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":451,"name":"Screening and evaluation of approved drugs as inhibitors of main protease of SARS-CoV-2","author":"Praveen Kumar Tripathia, Saurabh Upadhyay, Manju Singh, Siva Raghavendhar, Mohit Bhardwaj, Pradeep Sharma, Ashok Kumar Patela","doi":"10.1016\/j.ijbiomac.2020.08.166","abstract":"The COVID-19 pandemic caused by SARS-CoV-2 has emerged as a global catastrophe. The virus requires main protease for processing the viral polyproteins PP1A and PP1AB translated from the viral RNA. In search of a quick, safe and successful therapeutic agent; we screened various clinically approved drugs for the in-vitro inhibitory effect on 3CLPro which may be able to halt virus replication. The methods used includes protease activity assay, fluorescence quenching, surface plasmon resonance (SPR), Thermofluor\u00ae Assay, Size exclusion chromatography and in-silico docking studies. We found that Teicoplanin as most effective drug with IC50 ~ 1.5 \u03bcM. Additionally, through fluorescence quenching Stern\u2013Volmer quenching constant (KSV) for Teicoplanin was estimated as 2.5 \u00d7 105 L\u00b7mol\u22121, which suggests a relatively high affinity between Teicoplanin and 3CLPro protease. The SPR shows good interaction between Teicoplanin and 3CLPro with KD ~ 1.6 \u03bcM. Our results provide critical insights into the mechanism of action of Teicoplanin as a potential therapeutic against COVID-19. We found that Teicoplanin is about 10\u201320 fold more potent in inhibiting protease activity than other drugs in use, such as lopinavir, hydroxychloroquine, chloroquine, azithromycin, atazanavir etc. Therefore, Teicoplanin emerged as the best inhibitor among all drug molecules we screened against 3CLPro of SARS-CoV-2.","type":"Research","database":"PubMed","created":"2020-12-14"},{"id":450,"name":"Drug Discovery by Drug Repurposing: Combating COVID-19 in the 21st Century","author":"Nitesh Sanghai, Kashfia Shafiq, Geoffrey K. Tranmer","doi":"10.2174\/1389557520999200824103803","abstract":"Due to the rapidly developing nature of the current COVID-19 outbreak and its almost immediate humanitarian and economic toll, coronavirus drug discovery efforts have largely focused on generating potential COVID-19 drug candidates as quickly as possible. Globally, scientists are working day and night to find the best possible solution to treat the deadly virus. During the first few months of 2020, the SARS-CoV-2 outbreak quickly developed into a pandemic, with a mortality rate that was increasing at an exponential rate day by day. As a result, scientists have turned to a drug repurposing approach, to rediscover the potential use and benefits of existing approved drugs. Currently, there is no single drug approved by the U.S. Food and Drug Administration (FDA), for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) that causes COVID-19. Based on only in-vitro studies, several active drugs are already in the clinical pipeline, made possible by following the compassionate use of medicine protocols. This method of repurposing and the use of existing molecules like Remdesivir (GS-5734), Chloroquine, Hydroxychloroquine, etc. has proven to be a landmark in the field of drug rediscovery. In this review article we will discuss the repurposing of medicines for treating the deadly novel coronavirus (SARS-CoV-2).","type":"Review","database":"PubMed","created":"2020-12-14"},{"id":449,"name":"Molecular Docking and Virtual Screening based prediction of drugs for COVID-19","author":"Sekhar Talluri","doi":"10.2174\/1386207323666200814132149","abstract":"Aims: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications.\r\n\r\nBackground: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease are available.\r\n\r\nObjective: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs.\r\nMethods: List of drugs approved for clinical use was obtained from SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol and Rasmol.\r\nResults: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir have the highest binding affinity for the target main protease of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications.\r\nConclusion: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.","type":"Research","database":"PubMed","created":"2020-12-07"},{"id":448,"name":"Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2 in vitro infection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19","author":"Douglas Ferreira Sales-Medina, Ludmila Rodrigues Pinto Ferreira, Lav\u00ednia M. D. Romera, Karolina Ribeiro Gon\u00e7alves, Rafael V. C. Guido, Gilles Courtemanche, Marcos S. Buckeridge, \u00c9dison L. Durigon, Carolina B. Moraes, Lucio H. Freitas-Junior","doi":"10.1101\/2020.07.09.196337","abstract":"The disease caused by SARS-CoV2, covid-19, rapidly spreads worldwide, causing the\r\ngreatest threat to global public health in the last 100 years. This scenario has become\r\ncatastrophic as there are no approved vaccines to prevent the disease, and the main\r\nmeasures to contain the virus transmission are confinement and social distancing. One\r\npriority strategy is based on drug repurposing by pursuing antiviral chemotherapy that\r\ncan control transmission and prevent complications associated with covid-19. With this\r\naim, we performed a high content screening assay for the discovery of anti-SARS-CoV-2\r\ncompounds. From the 65 screened compounds, we have found four drugs capable to\r\nselectively inhibit SARS-CoV-2 in vitro infection: brequinar, abiraterone acetate,\r\nneomycin, and the extract of Hedera helix. Brequinar and abiraterone acetate had higher\r\ninhibition potency against SARS-CoV-2 than neomycin and Hedera helix extract,\r\nrespectively. Drugs with reported antiviral activity and in clinical trials for covid-19,\r\nchloroquine, ivermectin, and nitazoxanide, were also included in the screening, and the\r\nlast two were found to be non-selective. We used a data mining approach to build drughost molecules-biological function-disease networks to show in a holistic way how each\r\ncompound is interconnected with host node molecules and virus infection, replication,\r\ninflammatory response, and cell apoptosis. In summary, the present manuscript identified\r\nfour drugs with active inhibition effect on SARS-CoV-2 in vitro infection, and by network\r\nanalysis, we provided new insights and starting points for the clinical evaluation and\r\nrepurposing process to treat SARS-CoV-2 infection. ","type":"Research","database":"BioRxiv","created":"2020-12-07"},{"id":447,"name":"Prioritization of potential drugs targeting the SARS-CoV-2 main protease","author":"Yanjin Li, Yu Zhang, Yikai Han, Tengfei Zhang, Ranran Du","doi":"10.26434\/chemrxiv.12629858.v1","abstract":"Since its outbreak in 2019, the acute respiratory syndrome caused by SARS-Cov-2 has become a severe\r\nglobal threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this\r\npandemic disease. Here we employed a computational approach to prioritize potential inhibitors that\r\ndirectly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing\r\nthe viral RNA-translated polyprotein into functional proteins for viral replication. Based on a largescale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that\r\nmay suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known\r\nreplication inhibitor of hepatitis C virus (HCV), which is recently reported to inhibit SARS-Cov-2 as\r\nwell. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a\r\nnovel molecular similarity between this respiratory syndrome and neural activities. Our approach not\r\nonly provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals\r\nintriguing molecular patterns that are worth future explorations.\r\n","type":"Research","database":"ChemRxiv","created":"2020-12-07"},{"id":446,"name":"RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery","author":"Wei Zhu, Catherine Z. Chen, Kirill Gorshkov, Miao Xu, Donald C. Lo, Wei Zheng","doi":"10.1177\/2472555220942123","abstract":"COVID-19 respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global health issue since it emerged in December 2019. While great global efforts are underway to develop vaccines and to discover or repurpose therapeutic agents for this disease, as of this writing only the nucleoside drug remdesivir has been approved under Emergency Use Authorization to treat COVID-19. The RNA-dependent RNA polymerase (RdRP), a viral enzyme for viral RNA replication in host cells, is one of the most intriguing and promising drug targets for SARS-CoV-2 drug development. Because RdRP is a viral enzyme with no host cell homologs, selective SARS-CoV-2 RdRP inhibitors can be developed that have improved potency and fewer off-target effects against human host proteins and thus are safer and more effective therapeutics for treating COVID-19. This review focuses on biochemical enzyme and cell-based assays for RdRPs that could be used in high-throughput screening to discover new and repurposed drugs against SARS-CoV-2.","type":"Review","database":"PubMed","created":"2020-12-07"},{"id":445,"name":"Transcriptome-based drug repositioning for coronavirus disease 2019 (COVID-19)","author":"Zhilong Jia, Xinyu Song, Jinlong Shi, Weidong Wang, Kunlun He","doi":"10.1093\/femspd\/ftaa036","abstract":"The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5\u20137) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.","type":"Research","database":"PubMed","created":"2020-12-07"},{"id":444,"name":"Hypothetical targets and plausible drugs of coronavirus infection caused by SARS\u2010CoV\u20102","author":"Faezeh Almasi, Fatemeh Mohammadipanah","doi":"10.1111\/tbed.13734","abstract":"The world is confronting a dire situation due to the recent pandemic of the novel coronavirus disease (SARS\u2010CoV\u20102) with the mortality rate passed over 470,000. Attaining efficient drugs evolve in parallel to the understanding of the SARS\u2010CoV\u20102 pathogenesis. The current drugs in the pipeline and some plausible drugs are overviewed in this paper. Although different types of anti\u2010viral targets are applicable for SARS\u2010CoV\u20102 drug screenings, the more promising targets can be considered as 3C\u2010like main protease (3Cl protease) and RNA polymerase. The remdesivir could be considered the closest bifunctional drug to the provisional clinical administration for SARS\u2010CoV\u20102. The known molecular targets of the SARS\u2010CoV\u20102 include fourteen targets, while four molecules of angiotensin\u2010converting enzyme 2 (ACE2), cathepsin L, 3Cl protease and RNA\u2010dependent RNA polymerase (RdRp) are suggested as more promising potential targets. Accordingly, dual\u2010acting drugs as an encouraging solution in drug discovery are suggested. Emphasizing the potential route of SARS\u2010CoV\u20102 infection and virus entry\u2010related factors like integrins, cathepsin and ACE2 seems valuable. The potential molecular targets of each phase of the SARS\u2010CoV\u20102 life cycle are discussed and highlighted in this paper. Much progress in understanding the SARS\u2010CoV\u20102 and molecular details of its life cycle followed by the identification of new therapeutic targets are needed to lead us to an efficient approach in anti\u2010SARS\u2010CoV\u20102 drug discovery.","type":"Review","database":"PubMed","created":"2020-12-07"},{"id":443,"name":"Intranasal Antiviral Drug Delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review","author":"Thomas S. Higgins, Arthur W. Wu, Elisa A. Illing, Kevin J. Sokoloski, Bree A. Weaver, Benjamin P. Anthony, Nathan Hughes,  Jonathan Y. Ting","doi":"10.1177\/0194599820933170","abstract":"Objective\r\nTo provide a state of the art review of intranasal antiviral drug delivery and to discuss current applications, adverse reactions, and future considerations in the management of coronavirus disease 2019 (COVID-19).\r\n\r\nData Sources\r\nPubMed, Embase, and Clinicaltrials.gov search engines.\r\n\r\nReview Methods\r\nA structured search of the current literature was performed of dates up to and including April 2020. Search terms were queried as related to topics of antiviral agents and intranasal applications. A series of video conferences was convened among experts in otolaryngology, infectious diseases, public health, pharmacology, and virology to review the literature and discuss relevant findings.\r\n\r\nConclusions\r\nIntranasal drug delivery for antiviral agents has been studied for many years. Several agents have broad-spectrum antiviral activity, but they still require human safety and efficacy trials prior to implementation. Intranasal drug delivery has potential relevance for future clinical trials in the settings of disease spread prevention and treatment of SARS-CoV-2 and other viral diseases.\r\n\r\nImplications for Practice\r\nIntranasal drug delivery represents an important area of research for COVID-19 and other viral diseases. The consideration of any potential adverse reactions is paramount.","type":"Review","database":"PubMed","created":"2020-12-07"},{"id":442,"name":"Application prospect of polysaccharides in the development of anti-novel coronavirus drugs and vaccines","author":"Xiangyan Chen, Wenwei Han, Guixiang Wang, Xia Zhaoa","doi":"10.1016\/j.ijbiomac.2020.07.106","abstract":"Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, it has spread rapidly worldwide and poses a great threat to public health. This is the third serious coronavirus outbreak in <20 years, following SARS in 2002\u20132003 and MERS in 2012. So far, there are almost no specific clinically effective drugs and vaccines available for COVID-19. Polysaccharides with good safety, immune regulation and antiviral activity have broad application prospects in anti-virus, especially in anti-coronavirus applications. Here, we reviewed the antiviral mechanisms of some polysaccharides, such as glycosaminoglycans, marine polysaccharides, traditional Chinese medicine polysaccharides, and their application progress in anti-coronavirus. In particular, the application prospects of polysaccharide-based vaccine adjuvants, nanomaterials and drug delivery systems in the fight against novel coronavirus were also analyzed and summarized. Additionally, we speculate the possible mechanisms of polysaccharides anti-SARS-CoV-2, and propose the strategy of loading S or N protein from coronavirus onto polysaccharide capped gold nanoparticles vaccine for COVID-19 treatment. This review may provide a new approach for the development of COVID-19 therapeutic agents and vaccines.","type":"Review","database":"PubMed","created":"2020-12-07"},{"id":441,"name":"Major Neurologic Adverse Drug Reactions, Potential Drug\u2013Drug Interactions and Pharmacokinetic Aspects of Drugs Used in COVID-19 Patients with Stroke: A Narrative Review","author":"Ghasemiyeh P, Borhani-Haghighi A, Karimzadeh I, Mohammadi-Samani S, Vazin A, Safari A, Qureshi AI","doi":"https:\/\/doi.org\/10.2147\/TCRM.S259152","abstract":"Stroke has been considered as one of the underlying diseases that increases the probability of severe infection and mortality. Meanwhile, there are ongoing reports of stroke subsequent to COVID-19 infection. In this narrative paper, we reviewed major neurologic adverse drug reactions (ADRs) and pharmacokinetics of drugs which are routinely used for COVID-19 infection and their potential drug\u2013drug interactions (PDDIs) with common drugs used for the treatment of stroke. It is highly recommended to monitor patients on chloroquine (CQ), hydroxychloroquine (HCQ), antiviral drugs, and\/or corticosteroids about initiation or progression of cardiac arrhythmias, delirium, seizure, myopathy, and\/or neuropathy. In addition, PDDIs of anti-COVID-19 drugs with tissue plasminogen activator (tPA), anticoagulants, antiaggregants, statins, antihypertensive agents, and iodine-contrast agents should be considered. The most dangerous PDDIs were interaction of lopinavir\/ritonavir or atazanavir with clopidogrel, prasugrel, and new oral anticoagulants (NOACs).","type":"Review","database":"PubMed","created":"2020-12-07"},{"id":440,"name":"Identifying SARS-CoV-2 entry inhibitors through drug repurposing screens of SARS- S 2 and MERS-S pseudotyped particles","author":"Catherine Z. Chen, Miao Xu, Manisha Pradhan , Kirill Gorshkov, Jennifer Petersen, Marco R. Straus, Wei Zhu, Paul Shinn, Hui Guo, Min Shen, Carleen Klumpp-Thomas, Samuel G. Michael, Joshua Zimmerberg, Wei Zheng, Gary R. Whittaker ","doi":"10.1101\/2020.07.10.197988","abstract":"While vaccine development will hopefully quell the global pandemic of COVID-19 caused by\r\nSARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are \r\nurgently needed. Here, inhibitors of spike (S) mediated cell entry were identified in a high\r\nthroughput screen of an approved drugs library with SARS-S and MERS-S pseudotyped particle\r\nentry assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib,\r\ntrimipramine, colforsin, and ingenol) to be broad spectrum inhibitors for spike-mediated entry.\r\nThis work should contribute to the development of effective treatments against the initial stage of\r\nviral infection, thus reducing viral burden in COVID-19 patients. ","type":"Research","database":"BioRxiv","created":"2020-12-01"},{"id":439,"name":"Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing study","author":"Rameez Jabeer Khan, Rajat Kumar Jha, Ekampreet Singh, Monika Jain, Gizachew Muluneh Amera, Rashmi Prabha Singh, Jayaraman Muthukumaran, Amit Kumar Singh","doi":"10.1080\/07391102.2020.1814870","abstract":"The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (\u0394G), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM\/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of \u2212259.522\u2009\u00b1\u200917.579 and \u2212154.051\u2009\u00b1\u200933.628\u2009kJ\/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.","type":"Research","database":"PubMed","created":"2020-11-23"},{"id":438,"name":"Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2","author":"Mohammad M. Ghahremanpour, Julian Tirado-Rives, Maya Deshmukh, Joseph A. Ippolito, Chun-Hui Zhang, Israel Cabeza de Vaca, Maria-Elena Liosi,  Karen S. Anderson,  William L. Jorgensen","doi":"10.1101\/2020.08.28.271957","abstract":"A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with Mpro, 17 were chosen for evaluation in a kinetic assay for Mpro inhibition. Remarkably 14 of the compounds at 100-\u03bcM concentration were found to reduce the enzymatic activity and 5 provided IC50 values below 40 \u03bcM: manidipine (4.8 \u03bcM), boceprevir (5.4 \u03bcM), lercanidipine (16.2 \u03bcM), bedaquiline (18.7 \u03bcM), and efonidipine (38.5 \u03bcM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1\u2019, and P2 pockets of Mpro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.","type":"Research","database":"BioRxiv","created":"2020-11-23"},{"id":437,"name":"Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)","author":" Gabriela de Lima Menezes, Roosevelt Alves da Silva","doi":"10.1080\/07391102.2020.1792992","abstract":"Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19.","type":"Research","database":"PubMed","created":"2020-11-18"},{"id":436,"name":"Progress in the Research and Development of Anti-COVID-19 Drugs","author":"Lianzhou Huang, Yuanqiu Chen, Ji Xiao, Weisheng Luo, Feng Li, Yuan Wang, Yiliang Wang, Yifei Wang, Guangzhou Jin","doi":"10.3389\/fpubh.2020.00365","abstract":"The outbreaks of COVID-19 due to SARS-CoV-2 has caused serious physical and psychological damage to global human health. COVID-19 spread rapidly around the world in a short time. Confronted with such a highly infectious respiratory disease, the research and development of anti-COVID-19 drugs became an urgent work due to the lack of specific drugs for the treatment of COVID-19. Nevertheless, several existing drugs are available to relieve the clinical symptoms of COVID-19. We reviewed information on selected anti-SARS-CoV-2 candidate therapeutic agents published until June 2, 2020. We also discussed the strategies of the development of anti-COVID-19 drugs in the future. Our review provides a novel insight into the future development of a safer, efficient, and toxic-less anti-COVID-19 drug.","type":"Review","database":"PubMed","created":"2020-11-18"},{"id":435,"name":"Molecular Insights into Small Molecule Drug Discovery for SARS\u2010CoV\u20102","author":"Haibin Su,  Hailei Su,  Feng Zhou,  Ziru Huang,  Xiaohua Ma,  Kathiresan Natarajan,  Minchuan Zhang,  Yong Huang","doi":"10.1002\/anie.202008835","abstract":"The mainstream approach to antiviral drugs against COVID\u201019 is to focus on key stages of the SARS\u2010CoV\u20102 life cycle. The vast majority of candidates under investigation are repurposed from agents of other indications. Understanding of protein\u2010inhibitor interactions at molecular scale will provide crucial insights for drug discovery to stop this pandemic. In this article, we summarize and analyze the most recent structural data on several viral targets with the presence of promising inhibitors for COVID\u201019 in the perspective of modes of action (MOA) to unravel insightful mechanistic features with atomistic resolution. The targets include spike glycoprotein and various host proteases mediating the entry of the virus into the cells, viral chymotrypsin\u2010 and papain\u2010like proteases, and RNA dependent RNA polymerase. The main purpose of this review is to present detailed MOA analysis to inspire fresh ideas for both de novo drug design and optimization of known scaffolds to combat COVID\u201019.","type":"Review","database":"PubMed","created":"2020-11-18"},{"id":434,"name":"Drugs against SARS\u2010CoV\u20102: What do we know about their mode of action?","author":"Coralie Valle, Baptiste Martin, Franck Touret, Ashleigh Shannon, Bruno Canard, Jean\u2010Claude Guillemot, Bruno Coutard, Etienne Decroly","doi":"10.1002\/rmv.2143","abstract":"The health emergency caused by the recent Covid\u201019 pandemic highlights the need to identify effective treatments against the virus causing this disease (SARS\u2010CoV\u20102). The first clinical trials have been testing repurposed drugs that show promising anti\u2010SARS\u2010CoV\u20102 effects in cultured cells. Although more than 2400 clinical trials are already under way, the actual number of tested compounds is still limited to approximately 20, alone or in combination. In addition, knowledge on their mode of action (MoA) is currently insufficient. Their first results reveal some inconsistencies and contradictory results and suggest that cohort size and quality of the control arm are two key issues for obtaining rigorous and conclusive results. Moreover, the observed discrepancies might also result from differences in the clinical inclusion criteria, including the possibility of early treatment that may be essential for therapy efficacy in patients with Covid\u201019. Importantly, efforts should also be made to test new compounds with a documented MoA against SARS\u2010CoV\u20102 in clinical trials. Successful treatment will probably be based on multitherapies with antiviral compounds that target different steps of the virus life cycle. Moreover, a multidisciplinary approach that combines artificial intelligence, compound docking, and robust in\u2009vitro and in\u2009vivo assays will accelerate the development of new antiviral molecules. Finally, large retrospective studies on hospitalized patients are needed to evaluate the different treatments with robust statistical tools and to identify the best treatment for each Covid\u201019 stage. This review describes different candidate antiviral strategies for Covid\u201019, by focusing on their mechanism of action.","type":"Review","database":"PubMed","created":"2020-11-18"},{"id":433,"name":"Potential small\u2010molecule drugs as available weapons to fight novel coronavirus (2019\u2010nCoV): A review","author":"Vahid Rahimkhoei,  Nassrollah Jabbari,  Aynaz Nourani,  Sina Sharifi,  Ali Akbari","doi":"10.1002\/cbf.3576","abstract":"Since the new coronavirus known as 2019\u2010nCoV (severe acute respiratory syndrome coronavirus 2, SARS\u2010CoV\u20102) has widely spread in Wuhan, China, with severe pneumonia, scientists and physicians have made remarkable efforts to use various options such as monoclonal antibodies, peptides, vaccines, small\u2010molecule drugs and interferon therapies to control, prevent or treatment infections of 2019\u2010nCoV. However, no vaccine or drug has yet been confirmed to completely treat 2019\u2010nCoV. In this review, we focus on the use of potential available small\u2010molecule drug candidates for treating infections caused by 2019\u2010nCoV.","type":"Review","database":"PubMed","created":"2020-11-18"},{"id":432,"name":"Molecular docking and simulation studies on SARS-CoV-2 M pro  reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19","author":"Kiran Bharat Lokhande, Sayali Doiphode, Renu Vyas, K. Venkateswara Swamy","doi":"10.1080\/07391102.2020.1805019","abstract":"The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30 th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 M pro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repur- posing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX,http:\/\/www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti- viral drug libraries interact with SARS-CoV-2 M pro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynam- ics simulations of 100ns revealed the mean RMSD value of 2.25 \u00c5 for all the complex systems. This shows that lead compounds bound tightly within the M pro cavity and thus having conformational stability. Glutamic acid (Glu166) of M pro is a key residue to hold and form a stable complex of reported lead com- pounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 M pro .","type":"Research","database":"PubMed","created":"2020-11-09"},{"id":431,"name":"Potential Binding Efficiency of Antiviral Drug Lopinavir Targeted to the Catalytic Dyad, His41 - Cys145 of SARS CoV -2 Main Protease","author":"Muthu Raj S, Manohar M, Mohan M, Ganesh P, Marimuthu K","doi":"10.26434\/chemrxiv.12453644.v1","abstract":"The spread of SARS CoV 2 across the globe rushed the scientific community to find out\r\nthe potential inhibitor for controlling the viral disease. The main protease (Mpro) or\r\nChymotrypsin protease (3CLpro) is involved in the cleavage of polyproteins, duplication of\r\nintracellular materials and release of nonstructural proteins. Cys-His catalytic dyad is located in\r\nthe SARS-CoV Mpro which is the substrate-binding site located in domains I and II. There are\r\nmany approved drugs that have their active protease inhibition capability. The targeting of the\r\nactive site of the main protease is the better option to fight against the viral population.\r\nLopinavir, ritonavir, Remdesivir and Chloroquine are some of the drug candidates considered to\r\nbe involved in the treatment of SARS CoV 2 under emergency situation as a trial basis. In the\r\npresent investigation we used lopinavir as a drug to bind the catalytic dyad His41, Cys145 of\r\nmain protease. The minimum binding of energy of -11.45 kcal\/mol observed with the binding\r\nof Cys145 and -10.93 kcal\/mol was noted with the residue His41. The inhibition constant was\r\nalso found to be relevant to the binding efficiency of the drug. This is considered to be a model\r\ndrug target which is initiating the finding of many new drugs to target the current outbreak\r\ncreated by the virus SARS.CoV - 2.","type":"Research","database":"ChemRxiv","created":"2020-11-02"},{"id":430,"name":"Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2","author":"Shiyong Fan, Dian Xiao, Yanming Wang, Lianqi Liu, Xinbo Zhou, Wu Zhong ","doi":"10.4155\/fmc-2020-0158","abstract":"SARS-CoV-2 has been widely spread around the world and COVID-19 was declared a global pandemic by the WHO. Limited clinically effective antiviral drugs are available now. The development of anti-SARS-CoV-2 drugs has become an urgent work worldwide. At present, potential therapeutic targets and drugs for SARS-CoV-2 are continuously reported, and many repositioning drugs are undergoing extensive clinical research, including remdesivir and chloroquine. On the other hand, structures of many important viral target proteins and host target proteins, including that of RdRp and Mpro were constantly reported, which greatly promoted structure-based drug design. This paper summarizes the current research progress and challenges in the development of anti-SARS-CoV-2 drugs, and proposes novel short-term and long-term drug research strategies.","type":"Review","database":"PubMed","created":"2020-11-02"},{"id":429,"name":"Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach","author":"Syed Ovais Aftab, Muhammad Zubair Ghouri, Muhammad Umer Masood, Zeshan Haider, Zulqurnain Khan, Aftab Ahmad, Nayla Munawar ","doi":"10.1186\/s12967-020-02439-0","abstract":"Background\r\nThe Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) outbreak originating in Wuhan, China, has raised global health concerns and the pandemic has now been reported on all inhabited continents. Hitherto, no antiviral drug is available to combat this viral outbreak.\r\n\r\nMethods\r\nKeeping in mind the urgency of the situation, the current study was designed to devise new strategies for drug discovery and\/or repositioning against SARS-CoV-2. In the current study, RNA-dependent RNA polymerase (RdRp), which regulates viral replication, is proposed as a potential therapeutic target to inhibit viral infection.\r\n\r\nResults\r\nEvolutionary studies of whole-genome sequences of SARS-CoV-2 represent high similarity (>\u200990%) with other SARS viruses. Targeting the RdRp active sites, ASP760 and ASP761, by antiviral drugs could be a potential therapeutic option for inhibition of coronavirus RdRp, and thus viral replication. Target-based virtual screening and molecular docking results show that the antiviral Galidesivir and its structurally similar compounds have shown promise against SARS-CoV-2.\r\n\r\nConclusions\r\nThe anti-polymerase drugs predicted here\u2014CID123624208 and CID11687749\u2014may be considered for in vitro and in vivo clinical trials.","type":"Research","database":"PubMed","created":"2020-11-02"},{"id":428,"name":"SARS-CoV-2: Repurposed Drugs and Novel Therapeutic Approaches\u2014Insights into Chemical Structure\u2014Biological Activity and Toxicological Screening","author":"Cristina Adriana Dehelean, Voichita Lazureanu, Dorina Coricovac, Marius Mioc, Roxana Oancea, Iasmina Marcovici, Iulia Pinzaru, Codruta Soica, Aristidis M. Tsatsakis, Octavian Cretu","doi":"10.3390\/jcm9072084","abstract":"SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic represents the primary public health concern nowadays, and great efforts are made worldwide for efficient management of this crisis. Considerable scientific progress was recorded regarding SARS-CoV-2 infection in terms of genomic structure, diagnostic tools, viral transmission, mechanism of viral infection, symptomatology, clinical impact, and complications, but these data evolve constantly. Up to date, neither an effective vaccine nor SARS-CoV-2 specific antiviral agents have been approved, but significant advances were enlisted in this direction by investigating repurposed approved drugs (ongoing clinical trials) or developing innovative antiviral drugs (preclinical and clinical studies). This review presents a thorough analysis of repurposed drug admitted for compassionate use from a chemical structure\u2014biological activity perspective highlighting the ADME (absorption, distribution, metabolism, and excretion) properties and the toxicophore groups linked to potential adverse effects. A detailed pharmacological description of the novel potential anti-COVID-19 therapeutics was also included. In addition, a comprehensible overview of SARS-CoV-2 infection in terms of general description and structure, mechanism of viral infection, and clinical impact was portrayed.","type":"Review","database":"PubMed","created":"2020-11-02"},{"id":427,"name":"Revisiting potential druggable targets against SARS\u2010CoV\u20102 and repurposing therapeutics under preclinical study and clinical trials: A comprehensive review","author":"Abdullah Al Mamun Sohag, Md Abdul Hannan, Sadaqur Rahman, Motaher Hossain, Mahmudul Hasan, Md Kawsar Khan, Amena Khatun, Raju Dash, Md Jamal Uddin","doi":"10.1002\/ddr.21709","abstract":"Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2), is one of the most contagious diseases in human historythat has already affected millions of lives worldwide. To date, no vaccines or effectivetherapeutics have been discovered yet that may successfully treat COVID-19patients or contain the transmission of the virus. Scientific communities across theglobe responded rapidly and have been working relentlessly to develop drugs andvaccines, which may require considerable time. In this uncertainty, repurposing theexisting antiviral drugs could be the best strategy to speed up the discovery of effec-tive therapeutics against SARS-CoV-2. Moreover, drug repurposing may leave somevital information on druggable targets that could be capitalized in target-based drugdiscovery. Information on possible drug targets and the progress on therapeutic andvaccine development also needs to be updated. In this review, we revisited thedruggable targets that may hold promise in the development of the anti-SARS-CoV-2agent. Progresses on the development of potential therapeutics and vaccines that areunder the preclinical studies and clinical trials have been highlighted. We anticipatethat this review will provide valuable information that would help to accelerate thedevelopment of therapeutics and vaccines against SARS-CoV-2 infection.","type":"Review","database":"PubMed","created":"2020-11-02"},{"id":426,"name":"SARS-CoV-2 Nucleocapsid Assembly Inhibitors: Repurposing Antiviral and Antimicrobial Drugs Targeting Nucleocapsid-RNA Interaction","author":"Debica Mukherjee, UPASANA RAY","doi":"10.26434\/chemrxiv.12587336.v1","abstract":"SARS-CoV-2 pandemic has become a serious concern due to high transmission of this virus\r\nand unavailability of any definitive drugs yet in clinics. While novel antivirals are under\r\ninvestigation stage, scientists are also rigorously trying to use drug repurposing as an option\r\nto fight against this highly infectious novel coronavirus. Several drugs are under regular use\r\nfor other diseases that are getting screened for their usability against SARS-CoV2. In this study\r\nwe have targeted SARS-CoV-2 nucleocapsid assembly to shortlist FDA approved drugs that\r\ncould be tested for inhibition of SARS-CoV-2 virus particles inside the host cell. We could\r\nshortlist seven antiviral and anti-microbial drugs. These showed good fit in docking studies\r\ninside the RNA binding cleft of the nucleocapsid protein. Also, these drugs have good\r\nlipophilic properties suggesting that they would enter the host cells. We propose that these\r\nshortlisted drugs could potentially compete out binding of viral RNA to nucleocapsid and thus\r\ninhibit successful virus assembly leading to poor virus progeny levels. ","type":"Research","database":"ChemRxiv","created":"2020-11-02"},{"id":425,"name":"An Integrative in Silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease","author":"Nemanja Djokovic, Dusan Ruzic, Teodora Djikic, Sandra Cvijic, Jelisaveta Ignjatovic, Svetlana Ibric, Katarina Baralic, Aleksandra Buha Djordjevic, Marijana Curcic, Danijela Djukic-Cosic, Katarina Nikolic","doi":"10.26434\/chemrxiv.12578672.v1","abstract":"Aims: An infectious disease (COVID-19) caused by the coronavirus SARS-CoV-2 emerged in Wuhan,\r\nChina in December 2019. Currently, SARS-CoV-2 infected more than 9 million people and caused more\r\nthan 450 000 deaths. Considering the urgent need for novel therapeutics, drug repurposing approach\r\nmight offer rapid solutions comparing to de novo drug design. In this study, we investigated an integrative\r\nin silico drug repurposing approach as a valuable tool for rapid selection of potential candidates against\r\nSARS-CoV-2 Main Protease (Mpro).\r\n\r\nMain methods: To screen FDA-approved drugs, we designed an integrative in silico drug repurposing\r\napproach implementing structure-based molecular modelling techniques, physiologically-based\r\npharmacokinetic (PBPK) modelling of drugs disposition and data-mining analysis of drug-gene-COVID19 association.\r\n\r\nKey findings: Through the presented approach, 43 candidates with potential inhibitory effect on Mpro\r\nwere selected and further evaluated according to the predictions of tissue disposition, drug-gene-COVID19 associations and potential pleiotropic effects. We singled out 9 FDA approved drugs as the most\r\npromising for their profiling in COVID-19 drug discovery campaigns. Our results were in agreement with\r\ncurrent experimental findings, which validate the applied integrative approach and may support clinical\r\ndecisions for a novel epidemic wave of COVID-19.\r\n\r\nSignificance: To the best of our knowledge, this is the first integrative in silico repurposing study for\r\nCOVID-19 with a clear advantage in linking structure-based molecular modeling of Mpro inhibitors with\r\npredictions of tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects\r\nof selected candidates.","type":"Research","database":"ChemRxiv","created":"2020-11-02"},{"id":424,"name":"SARS-CoV-2: An Update on Potential Antivirals in Light of SARS-CoV Antiviral Drug Discoveries","author":"Hatem A. Elshabrawy","doi":"10.3390\/vaccines8020335","abstract":" Coronaviruses (CoVs) are a group of RNA viruses that are associated with different\r\ndiseases in animals, birds, and humans. Human CoVs (HCoVs) have long been known to be\r\nthe causative agents of mild respiratory illnesses. However, two HCoVs associated with severe\r\nrespiratory diseases are Severe Acute Respiratory Syndrome-CoV (SARS-CoV) and Middle East\r\nRespiratory Syndrome-CoV (MERS-CoV). Both viruses resulted in hundreds of deaths after spreading\r\nto several countries. Most recently, SARS-CoV-2 has emerged as the third HCoV causing severe\r\nrespiratory distress syndrome and viral pneumonia (known as COVID-19) in patients from Wuhan,\r\nChina, in December 2019. Soon after its discovery, SARS-CoV-2 spread to all countries, resulting in\r\nmillions of cases and thousands of deaths. Since the emergence of SARS-CoV, many research groups\r\nhave dedicated their resources to discovering effective antivirals that can treat such life-threatening\r\ninfections. The rapid spread and high fatality rate of SARS-CoV-2 necessitate the quick discovery of\r\neffective antivirals to control this outbreak. Since SARS-CoV-2 shares 79% sequence identity with\r\nSARS-CoV, several anti-SARS-CoV drugs have shown promise in limiting SARS-CoV-2 replication\r\nin vitro and in vivo. In this review, we discuss antivirals described for SARS-CoV and provide an\r\nupdate on therapeutic strategies and antivirals against SARS-CoV-2. The control of the current\r\noutbreak will strongly depend on the discovery of effective and safe anti-SARS-CoV-2 drugs.\r\n","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":423,"name":"Overview of therapeutic drug research for COVID-19 in China","author":"Heng Li, Li Yang, Fei-fei Liu, Xin-na Ma, Pei-lan He, Wei Tang, Xian-kun Tong, Jian-ping Zuo","doi":"10.1038\/s41401-020-0438-y","abstract":"Since the outbreak of novel coronavirus pneumonia (COVID-19) in December 2019, more than 2,500,000 people worldwide have been diagnosed with SARS-CoV-2 as of April 22. In response to this epidemic, China has issued seven trial versions of diagnosis and treatment protocol for COVID-19. According to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional Chinese medicine, which have been reported with good clinical treatment effects. Moreover, with further understanding of SARS-CoV-2 virus, new drugs targeting specific SARS-CoV-2 viral components arise and investigations on these novel anti-SARS-CoV-2 agents are also reviewed.","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":422,"name":"Profiles of COVID-19 clinical trials in the Chinese Clinical Trial Registry","author":"Peng Xu, Xiangyu Xing, Keying Yu, Zhiguo Lv, Huijing Cui, Yuhang Shi, Tianying Chang, Dongmei Zhang, Yibin Zhang, Kai Wang, Jing Lu, Qingxia Huang, Xiangyan Li, Yingzi Cui, Li Shi, Tan Wang, Junqi Niu, Jian Wang ","doi":"10.1080\/22221751.2020.1791736","abstract":"The COVID-19 pandemic has caused a global public health crisis. There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the COVID-19 pandemic. The Chinese scientists supported by private and government resources have adopted extensive efforts to identify effective drugs against the virus. To date, a large number of clinical trials addressing various aspects of COVID19 have been registered in the Chinese Clinical Trial Registry (ChiCTR), including more than 200 interventional studies. Under such an urgent circumstance, the scope and quality of these clinical studies vary significantly. Hence, this review aims to make a comprehensive analysis on the profiles of COVID-19 clinical trials registered in the ChiCTR, including a wide range of characteristics. Our findings will provide a useful summary on these clinical studies since most of these studies will encounter major challenges from the design to completion. It will be a long road for the outcomes of these studies to be published and international collaboration will help the ultimate goals of developing new vaccines and anti-viral drugs.","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":421,"name":"Drug treatment of coronavirus disease 2019 (COVID-19) in China.","author":"Zhe Jin, Jing-Yi Liu, Rang Feng, Lu Ji, Zi-Li Jin, Hai-Bo Li","doi":"10.1016\/j.ejphar.2020.173326","abstract":"Since December 2019, the coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syn-drome Coronavirus 2 (SARS-CoV-2) has spread throughout China as well as other countries. More than 8,700,000 confirmed COVID-19 cases have been recorded worldwide so far, with much more cases popping up overseas than those inside. As the initial epicenter in the world, China has been combating the epidemic for a relatively longer period and accumulated valuable experience in prevention and control of COVID-19. This article reviewed the clinical use, mechanism and efficacy of the clinically approved drugs recommended in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (DTPNCP) released by National Health Commission of P.R. China, and the novel therapeutic agents now undergoing clinical trials approved by China National Medical Products Administration (NMPA) to evaluate experimental treatment for COVID-19. Reviewing the progress in drug development for the treatment against COVID-19 in China may provide insight into the epidemic control in other countries.","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":420,"name":"Genetic Algorithm-Based Docking of Potent Inhibitors Against SARS-CoV-2 Main Protease: A Comparison Between Natural Products and Synthetic Drugs.","author":"Pragadeeshwara Rao R, Tinku Basu","doi":"10.26434\/chemrxiv.12526592.v1","abstract":"The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused coronavirus disease-2019\r\n(COVID-19) pandemic. Despite the intensive research currently, there are no therapeutics and vaccines\r\navailable. As the main protease (MPro) plays a vital role in SARS-CoV-2, it is an attractive drug target. Herein\r\nwe report, potential inhibitors form natural products and synthetic drugs against MPro. In detail, we studied the\r\ninteraction of inhibitors (Curcumin, Theaflavin, Deserpidine, Betulinic acid, Sinigrin, Emodin, Leptodactylone,\r\nSynthetic drugs, Lopinavir, Ritonavir, Indinavir, Amprenavir, Darunavir, Nelfinavir, Remdesivir, Saquinavir,\r\nSivelestat, Galidesivir, and Favipiravir) with the catalytic site of MPro. Lastly, ADME (Absorption, Distribution,\r\nMetabolism, and Excretion) properties of Natural products and synthetic drugs are explored. We identified\r\neight potential inhibitors against MPro\r\n.","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":419,"name":"An in-silico evaluation of COVID-19 main protease with clinically approved drugs","author":"Tachoua Wafa, Kabrine Mohamed, Mamona Mushtaq, Zaheer Ul-Haq","doi":"10.1016\/j.jmgm.2020.107758","abstract":"A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in\r\nDecember 2019, continues to spread at a rapid rate worldwide. There are no specific therapies\r\navailable and investigations regarding the treatment of this disease are still lacking. In order to\r\nidentify a novel potent inhibitor, we performed blind docking studies on the main virus\r\nprotease Mpro with eight approved drugs belonging to four pharmacological classes such as:\r\nanti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied\r\ncompounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease.\r\nWhen docked against Mpro crystal structure, these two compounds revealed a minimum\r\nbinding energy of -8.87 and -8.71 kcal\/mol with 168 and 256 binding modes detected in the\r\nbinding substrate pocket, respectively. Further, to study the interaction mechanism and\r\nconformational dynamics of protein-ligand complexes, Molecular dynamic simulation and\r\nMM\/PBSA binding free calculations were performed. Our results showed that\r\nboth Lymecycline and Mizolastine bind in the active site. And exhibited good binding\r\naffinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness\r\nproperties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like\r\nprotease (3CLpro) of SARS-CoV-2. \r\n","type":"Research","database":"PMC","created":"2020-10-26"},{"id":418,"name":"Potential Docking Affinity of Three Approved Drugs Against SARS-CoV-2 for COVID-19 Treatment","author":"Venkata Rachakulla, Hemanjali Rachakulla","doi":"10.26434\/chemrxiv.12548063.v1","abstract":"Potential Docking Affinity of three Approved Drugs against SARS-CoV-2 for COVID-19 treatment. Venkata\r\nSambasiva Rao Rachakulla1\r\n, Hemanjali Devi Rachakulla2 1Department of Math, Greene County High School,\r\nGreensboro, GA, 30642 USA. 2Department of Science, Jonesboro High School, Jonesboro, GA, 30236, USA.\r\n1\r\nAuthor for correspondence email: rachakullav@gmail.com 2\r\nAuthor email: hemanjali27@gmail.com Abstract\r\nObjectives: The availability of a safe and effective drug for COVID-19 is well-recognized as an additional tool\r\nto contribute to the control of the pandemic. At the same time, the challenges and efforts needed to rapidly\r\ndevelop, evaluate, and produce this at scale are enormous. It is vital that we evaluate as many vaccines as\r\npossible as we cannot predict how many will turn out to be viable. Methods: In this study, we have measured\r\nthe virtual interaction of crystal data structures of protein downloaded from protein data bank (PDB ID 7BRP)\r\nwith corticosteroid drug candidates approved by FDA for other medical purposes which have less side effects.\r\nThe results are analyzed in contrast some drugs candidates currently using for the treatment of COVID-19.\r\nResults: The binding energies in kilocalories\/mole obtained from the docking of 7BRP protease with ligands\r\nunder investigation Betamethasone Phosphate (-6.9), Fluticasone (-6.1) and Dexamethasone (-5.9) and also\r\nwith currently using drug candidates Remdesivir(-6.5), Lopinavir (-6.0), Baceprivir(-5.7), Rabavirin(-6),\r\nRitinovir(-5.3), Hydroxyquinoline(-5.0), Chloroquine (-4.7), Oseltamivir(-4.6), Favipiravir(-3.9). Discussion:\r\nThe docking results suggest a higher binding affinity of the drug molecules under investigation against\r\nSARS-CoV-2 in contrast with other drug candidates currently being used for the treatment of COVID-19. We\r\nhave analyzed bond interactions of protein-ligand from images in 10 modes of investigated drugs in contrast\r\nwith Remdesivir and also discussed the advantages of inhalation methods of drug fluticasone. Conclusion:\r\nFrom this study, it can be suggested that these drugs are promising candidates for antiviral treatment with\r\nhigh potential to fight against SARS-CoV-2 strain keeping in view various ways of administration of drugs\r\ncurrently practicing.\r\n","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":417,"name":"A promising antiviral candidate drug for the COVID-19 pandemic: Amini-review of remdesivir","author":"Chengyuan Liang, Lei Tian, Yuzhi Liu, Nan Hui, Guaiping Qiao, Han Li, Zhenfeng Shi, Yonghong Tang, Dezhu Zhang, Xiaolin Xie, Xu Zhao","doi":"10.1016\/j.ejmech.2020.112527","abstract":"Remdesivir (GS-5734), a viral RNA-dependent RNA polymerase (RdRP) inhibitor that can be used to treata variety of RNA virus infections, is expected to be an effective treatment for severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) infection. On May 1, 2020, The U.S. Food and Drug Administration(FDA) has granted Emergency Use Authorization (EUA) for remdesivir to treat COVID-19 patients. In lightof the COVID-19 pandemic, this review presents comprehensive information on remdesivir, includinginformation regarding the milestones, intellectual properties, anti-coronavirus mechanisms, preclinicalresearch and clinical trials, and in particular, the chemical synthesis, pharmacology, toxicology, phar-macodynamics and pharmacokinetics of remdesivir. Furthermore, perspectives regarding the use ofremdesivir for the treatment of COVID-19 are also discussed.","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":416,"name":"Tackling SARS-CoV-2: proposed targets and repurposed drugs","author":"Siddhi Joshi, Maithili Joshi, Mariam S Degani","doi":"10.4155\/fmc-2020-0147","abstract":"The SARS-CoV-2 pandemic, declared as a global health emergency by the WHO in February 2020, has currently infected more than 6 million people with fatalities near 371,000 and increasing exponentially, in absence of vaccines and drugs. The pathogenesis of SARS-CoV-2 is still being elucidated. Identifying potential targets and repurposing drugs as therapeutic options is the need of the hour. In this review, we focus on potential druggable targets and suitable therapeutics, currently being explored in clinical trials, to treat SARS-CoV-2 infection. A brief understanding of the complex interactions of both viral as well as host targets, and the possible repurposed drug candidates are described with an emphasis on understanding the mechanisms at the molecular level.","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":415,"name":"COVID-19: Review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking","author":"Giuseppe Magro","doi":"10.1016\/j.virusres.2020.198070","abstract":"SARS-CoV-2 is the agent responsible for COVID-19. The infection can be dived into three phases: mild infection,the pulmonary phase and the inflammatory phase. Treatment options for the pulmonary phase include:Hydroxychloroquine, Remdesivir, Lopinavir\/Ritonavir. The inflammatory phase includes therapeutic optionslike Tocilizumab, Anakinra, Baricitinib, Eculizumab, Emapalumab and Heparin. Human clinical trials arestarting to show some results, in some cases like that of Remdesivir and corticosteroids these are controversial.Coagulopathy is a common complication in severe cases, inflammation and coagulation are intertwined andcross-talking between these two responses is known to happen. A possible amplification of this cross-talking issuggested to be implicated in the severe cases that show both a cytokine storm and coagulopathy.","type":"Review","database":"PubMed","created":"2020-10-26"},{"id":414,"name":"In Silico Docking Studies of Antimalarial Drug Hydroxychloroquine to SARS-CoV Proteins :An Emerging Pandemic Worldwide","author":"Priyanka H. Jokhakar, Rishee Kalaria, Hiren K. Patel","doi":"10.26434\/chemrxiv.12488804.v1","abstract":"This computational study comprises screening and prediction of interaction of\r\nselected antimalarial drug hydroxychloroquine with targeted two proteins of coronavirus.\r\nOne is SARS enveloped E pantameric ion channel protein and another is SARS-CoV-2\r\nmain apoprotein protease. Both are vital for viral attachment and entry to the host cell for\r\ninfection. After molecular protein docking with different confirmations, stable interacting\r\ncomplex of ligand and macromolecules were obtained. Interacting Lysine, Threonine and\r\nTyrosine of E protein were found for participation of stable interaction with selected drug\r\nhaving docking affinity energy of -6.3kcal\/mol. For apoprotein protease stable confirmation\r\nwas screened out having bonding Threonine residue with same drug of energy -6.0\r\nkcal\/mol. Irreversible covalent bond formation and van der Waals interaction favours the\r\nselectivity and stability of both targeted proteins towards selected drug. Conventional as\r\nwell as hydrophobic interactions are found in Ligplot and Discovery studio analysis also\r\nindicates stabilized confirmations between ligand and drug. Thus, this study delivers the\r\nputative mechanism of the drug interactions to target proteins hence comprising landmark\r\nfor future investigation for antimalarial hydroxychloroquine as anti COVID 19 drug in this\r\nexperimental time.","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":413,"name":"Repositioning of 8565 Existing Drugs for COVID-19","author":"Kaifu Gao, Duc Duy Nguyen, Jiahui Chen, Rui Wang, Guo-Wei Wei","doi":"10.1021\/acs.jpclett.0c01579","abstract":"The coronavirus disease 2019 (COVID-19) pandemic\r\ncaused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has infected over 7.1 million people and led to over 0.4 million\r\ndeaths. Currently, there is no specific anti-SARS-CoV-2 medication.\r\nNew drug discovery typically takes more than 10 years. Drug\r\nrepositioning becomes one of the most feasible approaches for\r\ncombating COVID-19. This work curates the largest available\r\nexperimental data set for SARS-CoV-2 or SARS-CoV 3CL (main)\r\nprotease inhibitors. On the basis of this data set, we develop validated\r\nmachine learning models with relatively low root-mean-square error to\r\nscreen 1553 FDA-approved drugs as well as another 7012 investigational or off-market drugs in DrugBank. We found that many existing\r\ndrugs might be potentially potent to SARS-CoV-2. The druggability of\r\nmany potent SARS-CoV-2 3CL protease inhibitors is analyzed. This work offers a foundation for further experimental studies of\r\nCOVID-19 drug repositioning.","type":"Research","database":"PubMed","created":"2020-10-26"},{"id":411,"name":"In-Silico Interaction of Hydroxychloroquine Drug with Various Proteins of Coronavirus (SARS-CoV-2): A Computational Approaches to Combat COVID-19","author":"Rishee Kalaria, Hiren K. Patel","doi":"10.26434\/chemrxiv.12470381.v1","abstract":"Most human viral illnesses are a result of a pathogenic occurrence. Some of the diseases caused by these\r\ntransmissible events have infected millions of people around the world, with some contributing to elevated\r\nmorbidity\/mortality rates in humans. Changes in the viral proteins that act as host receptor ligands may promote\r\nspill over between organisms. Finding a remedy along with the putative mechanism to cure COVID-19 spread is\r\nthe urgent need of recent time. Even though limited amount of data are available, utilizing In silico approaches\r\ncan be promising for the action. In the present study, In silico approach were performed using receptor-binding\r\ndomain of Envelop protein, PLpro protein and Spike glycoprotein of SARS-CoV-2 and its interaction with drug\r\nHydroxychloroquine for hinders the epidemic. Based on available data of SARS-CoV and SARS-CoV-2, target\r\nproteins structure were predicted using homology modelling and further structures stabilization check using\r\nRamachandran plot. Identification of pockets and cavities in all potential targets performed using CASTp web\r\nserver and energy minimization was carried out in order to dock these potential targets with the candidate drug\r\nHydroxychloroquine using Patchdock web server. In silico docking study showed that hydroxychloroquine drug\r\ninteractions with SARS-CoV2 show a higher binding affinity with spike glycoprotein and PLPRO protein\r\ncompared to protein envelopes that could be ladder for potential targeting and synthesizing of another aniviral\r\ndrug. In silico methods used in this study, the efficacy of a wide variety of repositioned and\/or novel drug\r\ncandidates could also be tested prior to clinical evaluation.","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":410,"name":"In Silico Screening of Some Antiviral Phytochemicals as Drug Leads Against Covid-19","author":"Monjur Ahmed Laskar, Moriom Begam, Manabendra Dutta Choudhury","doi":"10.26434\/chemrxiv.12478568.v1","abstract":"Background: COVID-19 caused by SARS-CoV-2 in December 2019 has become a pandemichazard to the\r\ncommunity health. It is a respiratory difficulty causing fever, dry cough, fatigue,shortness of breath, muscle\r\naches and some instances lead to pneumonia. Coronaviruses havelarge viral RNA Genomes and are\r\nsingle-stranded positive-sense RNA viruses. The nsp10\/nsp16protein is an important target because it is\r\nessential for the virus to replicate, the papain-likeprotease (Nsp3), the main protease (Nsp5), the primary\r\nRNA-dependent RNA polymerase(Nsp12) are also attractive drug targets for this disease. The uses of\r\nphytochemicals astherapeutic agents have been increasing in recent years. Some antiviral phytochemicals\r\nweretaken based on literature survey for this study.Methods: ADME parameters and drug like nature of\r\nphytochemicals were screened usingSwissADME web tool. Three dimensional structures of targets are\r\ndownloaded from ProteinData Bank and docked with phytochemicals & control by using software\r\nFlexX.Results: Morin shows significant results in ADME screening and Drug likeness predictionstudies, it\r\nshows stable bonding pattern with all four targets in compare to other phytochemicalsand control, shows least\r\nscore in docking and forms maximum number of hydrogen bonds withthe active residues of the\r\nreceptors.Conclusion: Based on present observation of docking results, ADME parameters and drug\r\nlikenature, we suggest that morin may be a potent new drug candidate against Covid-19.","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":409,"name":"Approach Towards Drugs Repurposing: Docking Studies with Multiple Target Proteins Associated with SARS-CoV-2","author":"Shiwani Rana, Meghali Panwar, Kalyan Sundar Ghosh","doi":"10.26434\/chemrxiv.12469172.v1","abstract":"The current pandemic outbreak of COVID-19 due to viral infections by SARS-CoV-2 is now\r\nbecome associated with severe commotion on global healthcare and economy. In this extreme\r\nsituation when vaccine or drugs against COVID-19 are not available, the only quick and feasible\r\ntherapeutic alternative would be the drug repurposing approach. In the present work, in silico\r\nscreening of some antiviral and antiprotozoal drugs using Autodock docking tool was performed.\r\nTwo known antiviral drugs sorivudine and noricumazole B are predicted to bind to the active site\r\nof the viral proteases namely cysteine like protease or 3CL protease (3CLpro) and papain like\r\nprotease (PLpro) respectively with a highly favorable free energy of binding. Further, the\r\npromising molecules were subjected for checking their activity on other molecular targets like\r\nspike protein S1, RNA dependent RNA polymerase (RdRp) and angiotensin converting enzyme\r\n2 (ACE2) receptor. But the compounds were found not effective on rest other molecular targets.","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":408,"name":"Binding Mechanism and Structural Insights into the Identified Protein Target of Covid-19 with In-Vitro Effective Drug Ivermectin","author":"Parth Sarthi Sen Gupta, Satyaranjan Biswal, Saroj Kumar Panda, Abhik Kumar Ray, Malay Kumar Rana","doi":"10.26434\/chemrxiv.12463946.v1","abstract":"While an FDA approved drug Ivermectin was reported to dramatically reduce the cell line of SARS-CoV-2 by\r\n~5000 folds within 48 hours, the precise mechanism of action and the COVID-19 molecular target involved in\r\ninteraction with this in-vitro effective drug are unknown yet. Among 12 different COVID-19 targets studied\r\nhere, the RNA dependent RNA polymerase (RdRp) with RNA and Helicase NCB site show the strongest\r\naffinity to Ivermectin amounting -10.4 kcal\/mol and -9.6 kcal\/mol, respectively. Molecular dynamics of\r\ncorresponding protein-drug complexes reveals that the drug bound state of RdRp with RNA has better\r\nstructural stability than the Helicase NCB site, with MM\/PBSA free energy of -135.2 kJ\/mol, almost twice that\r\nof Helicase (-76.6 kJ\/mol). The selectivity of Ivermectin to RdRp is triggered by a cooperative interaction of\r\nRNA-RdRp by ternary complex formation. Identification of the target and its interaction profile with Ivermectin\r\ncan lead to more powerful drug designs for COVID-19 and experimental exploration.","type":"Research","database":"ChemRxiv","created":"2020-10-26"},{"id":407,"name":"Bcr-Abl tyrosine kinase inhibitor imatinib as a potential drug for COVID-19","author":"Nirmitee Mulgaonkar, Haoqi Wang, Samavath Mallawarachchi, Sandun Fernando, Byron Martina, Daniel Ruzek","doi":"10.1101\/2020.06.18.158196","abstract":"The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate\r\nneed for potent drugs. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial\r\nmechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary\r\ninteraction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is\r\nconsidered as a potential target for drug development. Based on in silico screening followed by in\r\nvitro studies, here we report that the existing FDA-approved Bcr-Abl tyrosine kinase inhibitor,\r\nimatinib, inhibits SARS-CoV-2 with an IC50 of 130 nM. We provide evidence that although\r\nimatinib binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein with an\r\naffinity at micromolar, i.e., 2.32 \u00b1 0.9 \u00b5M levels, imatinib does not directly inhibit the spike\r\nRBD:ACE2 interaction \u2013 suggesting a Bcr-Abl kinase-mediated fusion inhibition mechanism is\r\nresponsible for the inhibitory action. We also show that imatinib inhibits other coronaviruses,\r\nSARS-CoV, and MERS-CoV via fusion inhibition. Based on promising in vitro results, we\r\npropose the Abl tyrosine kinase inhibitor (ATKI), imatinib, to be a viable repurposable drug\r\nagainst COVID-19. ","type":"Research","database":"BioRxiv","created":"2020-10-23"},{"id":406,"name":"Computational drug repurposing for the identification of SARS-CoV-2 main protease inhibitors","author":"Diego Fiorucci, Eva Milletti, Francesco Orofino, Antonella Brizzi, Claudia Mugnaini, Federico Corelli","doi":"10.1080\/07391102.2020.1796805","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the known COVID-19 disease. Since currently no definitive therapies or vaccines for the SARS-CoV-2 virus are available, there is an urgent need to identify effective drugs against SARS-CoV-2 infection. One of the best-known targets available is the main protease of this virus, crucial for the processing of polyproteins codified by viral RNA. In this work, we used a computational virtual screening procedure for the repurposing of commercial drugs available in the DrugBank database as inhibitors of the SARS-CoV-2 main protease. Molecular docking calculations and molecular dynamics (MD) simulations have been applied. The computational model was validated through a self-docking procedure. The screening procedure highlighted five interesting drugs that showed a comparable or higher docking score compared to the crystallographic compound and maintained the protein binding during the MD runs. Amongst these drugs, Ritonavir has been used in clinical trials with patients affected by COVID-19 and Nelfinavir showed anti-SARS-CoV-2 activity. The five identified drugs could be evaluated experimentally as inhibitors of the SARS-CoV-2 main protease in view of a possible COVID-19 treatment.","type":"Research","database":"PubMed","created":"2020-10-12"},{"id":405,"name":"Potential drugs for the treatment of the novel coronavirus pneumonia (COVID-19) in China","author":"Xiaoqi Pana, Lan Dong, Lian Yanga, Dayi Chen, Cheng Peng","doi":"10.1016\/j.virusres.2020.198057","abstract":"The fight against the novel coronavirus pneumonia (namely COVID-19) that seriously harms human health is a common task for all mankind. Currently, development of drugs against the novel coronavirus (namely SARS-CoV-2) is quite urgent. Chinese medical workers and scientific researchers have found some drugs to play potential therapeutic effects on COVID-19 at the cellular level or in preliminary clinical trials. However, more fundamental studies and large sample clinical trials need to be done to ensure the efficacy and safety of these drugs. The adoption of these drugs without further testing must be careful. The relevant articles, news, and government reports published on the official and Preprint websites, PubMed and China National Knowledge Infrastructure (CNKI) databases from December 2019 to April 2020 were searched and manually filtered. The general pharmacological characteristics, indications, adverse reactions, general usage, and especially current status of the treatment of COVID-19 of those potentially effective drugs, including chemical drugs, traditional Chinese medicines (TCMs), and biological products in China were summarized in this review to guide reasonable medication and the development of specific drugs for the treatment of COVID-19.","type":"Review","database":"PubMed","created":"2020-10-12"},{"id":404,"name":"Prediction of SARS-CoV-2 Main Protease Inhibitors from Several Medicinal Plant Compounds by Drug Repurposing and Molecular Docking Approach.","author":"Sayma Farabi, Nihar Ranjan Saha, Noushin Anika Khan, Md. Hasanuzzaman.","doi":"10.26434\/chemrxiv.12440024.v1","abstract":"Coronaviruses are endemic in humans and infections normally mild, such as the common cold but cross-species transmission has produced some unusually virulent strains which now causing viral pneumonia and in serious cases even acute respiratory distress syndrome and death. SARS-CoV-2  is  the  most  threatening  issue  which  leads  the  world  to  an  uncertainty  alongside  thousands  of regular death scenes.  For this virus, death toll is increasing in. An effective vaccine to cure this virus is not yet available, thus requires concerted efforts at various scales. The viral Main Protease controls  Coronavirus  replication  and  is  a  proven  drug  discovery  target  for  SARS-CoV-2.  Here, comprehensive computational approaches including drug repurposing and molecular docking were employed  to  predict  the  efficacy  of  medicinal  plant-based  bioactive  compounds  against  SARS-CoV-2  Mpro.  Molecular  docking  was  performed  using  PyRx-autodock  vina  to  analyze  the inhibition probability. MPP (6LU7) was docked with 90 phytochemical compounds and docking was analysed by PyRx-autodock vina, Pymol version 1.7.4.5 Edu, and Biovia Discovery Studio 4.5. Furthermore, ADME analysis along with analysis of toxicity was also investigated to check the pharmacokinetics and drug-likeness properties of the antiviral phytochemicals. Remdesivir and lopinavir  were  used  as  standards  for  comparison.  Our  analyses  revealed  that  the  top  ten (Azadirachtin, -12.5kcal\/mol;  Rutin, -9  kcal\/mol;  Theaflavin, -9  kcal\/mol;  Astragalin, -8.8 kcal\/mol;  Isoquercitrin, -8.7  kcal\/mol;  Hyperoside, -8.6  kcal\/mol;  Baicalin, -8.4  kcal\/mol; Saponin, -8.3 kcal\/mol; Sennoside A, -8.3 kcal\/mol; Aloin, -8.2 kcal\/mol, while Remdesivir and Lopinavir  showed -8.2  and -7.9  kcal\/mol)  hits  might  serve  as  potential  anti-SARS-CoV-2  lead molecules for further optimization and drug development process to combat COVID-19. ","type":"Research","database":"ChemRxiv","created":"2020-10-12"},{"id":403,"name":"Structure Basis for Inhibition of SARS-CoV-2 by the Feline Drug GC376","author":"Xiaodong Luan, Weijuan Shang, Yifei Wang, Wanchao Yin, Yi Jiang, Siqin Feng, Yiyang Wang, Meixi Liu, Ruilin Zhou, Zhiyu Zhang, Feng Wang, Wang Cheng, Minqi Gao, Hui Wang, Wei Wu, Ran Tian, Zhuang Tian, Ye Jin, Hualiang Jiang, Leike Zhang, H. Eric Xu, Shuyang Zhang","doi":"10.1101\/2020.06.07.138677","abstract":"The pandemic of SARS-CoV-2 coronavirus disease-2019 (COVID-19) caused by SARS-COV-2 continues to ravage many countries in the world. Mpro is an indispensable protein for viral translation in SARS-CoV-2 and a potential target in high-specificity anti-SARS-CoV-2 drug screening. In this study, to explore potential drugs for treating COVID-19, we elucidated the structure of SARS-CoV-2 Mpro and explored the interaction between Mpro and GC376, an antiviral drug used to treat a range of coronaviruses in Feline via inhibiting Mpro. The availability and safety of GC376 were proved by biochemical and cell experiments in vitro. We determined the structure of an important protein, Mpro, in SARS-CoV-2, and revealed the interaction of GC376 with the viral substrate and inhibition of the catalytic site of SARS-CoV-2 Mpro.","type":"Research","database":"BioRxiv","created":"2020-10-12"},{"id":402,"name":"Guidance on Short\u2010Term Management of Atrial Fibrillation in Coronavirus Disease 2019","author":"Pattara Rattanawong, Win Shen, Hicham El Masry, Dan Sorajja, Komandoor Srivathsan, Arturo Valverde, Luis R. Scott","doi":"10.1161\/JAHA.120.017529","abstract":"Atrial fibrillation is a common clinical manifestation in hospitalized patients with coronavirus disease 2019 (COVID\u201019). Medications used to treat atrial fibrillation, such as antiarrhythmic drugs and anticoagulants, may have significant drug interactions with emerging COVID\u201019 treatments. Common unintended nontherapeutic target effects of COVID\u201019 treatment include potassium channel blockade, cytochrome P 450 isoenzyme inhibition or activation, and P\u2010glycoprotein inhibition. Drug\u2010drug interactions with antiarrhythmic drugs and anticoagulants in these patients may lead to significant bradycardia, ventricular arrhythmias, or severe bleeding. It is important for clinicians to be aware of these interactions, drug metabolism changes, and clinical consequences when choosing antiarrhythmic drugs and anticoagulants for COVID\u201019 patients with atrial fibrillation. The objective of this review is to provide a practical guide for clinicians who are managing COVID\u201019 patients with concomitant atrial fibrillation.","type":"Review","database":"PubMed","created":"2020-10-12"},{"id":401,"name":"Artesunate: could be an alternative drug to chloroquine in COVID-19 treatment?","author":"Tu\u011f\u00e7enur Uzun, Orcun Toptas ","doi":"10.1186\/s13020-020-00336-8","abstract":"SARS (Severe Acute Respiratory Syndrome Coronavirus)-CV-2 (2019-nCov), which showed up in China in December 2019 and spread all over the world, has becomed a serious health problem. An effective, safe and proven treatment has not yet been found. Chloroquine has been recommended by some authors to be used for the treatment of patients infected with this virus however chloroquine may have side effects and drug resistance problems. Artesunate is a semisynthetic derivative of artemisinin, an antimalarial drug. Artesunate was thought to be an effective treatment for covid-19 because of its anti-inflammatory activity, NF-\u03baB (nuclear Factor kappa B)-coronavirus effect and chloroquine-like endocytosis inhibition mechanism.","type":"Comment","database":"PubMed","created":"2020-10-12"},{"id":400,"name":"Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins","author":"Meenakshisundaram Balasubramaniam, Robert J. Shmookler Reis","doi":"10.26434\/chemrxiv.12084822.v2","abstract":"Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV).  While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections.  Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug).  Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling.  Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions.  We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.","type":"Research","database":"PubMed","created":"2020-10-12"},{"id":399,"name":"The potential of drug repositioning as a short-term strategy for the control and treatment of COVID-19 (SARS-CoV-2): a systematic review","author":"William Gustavo Lima, J\u00falio C\u00e9sar Moreira Brito, Joerg Overhage, Waleska Stephanie da Cruz Nizer ","doi":"10.1007\/s00705-020-04693-5","abstract":"The novel human coronavirus (SARS-CoV-2), the causative agent of COVID-19, has quickly become a threat to the public health and economy worldwide. Despite the severity of some cases, there are no current pathogen-specific antivirals available to treat the disease. Therefore, many studies have focused on the evaluation of the anti-SARS-CoV-2 activity of clinically available drugs. Here, we conducted a systematic review to describe the drug repositioning strategy against SARS-CoV-2 and to discuss the clinical impact of this approach in the current pandemic context. The systematic review was performed on March 23, 2020, using PubMed\/MEDLINE, Scopus, Cochrane Library, and Biblioteca Virtual de Sa\u00fade (BVS). The data were summarized in tables and critically analyzed. After the database search, 12 relevant studies were identified as eligible for the review. Among the drugs reported in these studies, 57 showed some evidence of antiviral activity. Antivirals, especially antiretrovirals, are the main class of therapeutic agents evaluated against COVID-19. Moreover, studies have reported the anti-SARS-CoV-2 activity of antitumor (16%; 9\/57), antimalarial (7%, 4\/57), and antibacterial (5%; 3\/57) agents. Additionally, seven pharmacological agents (chloroquine, tetrandrine, umifenovir (arbidol), carrimycin, damageprevir, lopinavir\/ritonavir) are in phase IV of clinical trials. Due to the evidence of the anti-SARS-CoV-2 activity of various clinically available agents, drug repositioning stands out as a promising strategy for a short-term response in the fight against the novel coronavirus.","type":"Review","database":"PubMed","created":"2020-10-12"},{"id":398,"name":"Tocilizumab for patients with COVID-19 pneumonia. The TOCIVID-19 prospective phase 2 trial","author":"Francesco Perrone, Maria Carmela Piccirillo, Paolo Antonio Ascierto, Carlo Salvarani, Roberto Parrella, Anna Maria Marata, Patrizia Popoli, Laurenzia Ferraris, Massimiliano M Marrocco Trischitta, Diego Ripamonti, Francesca Binda, Paolo Bonfanti, Nicola Squillace, Francesco Castelli, Maria Lorenza Muiesan, Miriam Lichtner, Carlo Calzetti, Nicola Duccio Salerno, Luigi Atripaldi, Marco Cascella, massimo costantini, Giovanni Dolci, Nicola Cosimo Facciolongo, Fiorentino Fraganza, Marco Massari, Vince","doi":"10.1101\/2020.06.01.20119149","abstract":"Background: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods: A multicentre, single-arm, hypothesis-driven phase 2 trial was planned to study the effect of Tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints). A cohort of patients consecutively enrolled after phase 2 was used as a validation dataset. A multivariable logistic regression was performed to generate hypotheses, while controlling for possible confounders. Results: out of 301 patients in phase 2 intention-to-treat (ITT) analysis, 180 (59.8%) received tocilizumab. With 67 death events, lethality rates were 18.4% (97.5%CI: 13.6-24.0, P=0.52) and 22.4% (97.5%CI: 17.2-28.3, P<0.001) at 14 and 30 days. Lethality rates were lower in the validation dataset, including 920 patients. No signal of specific drug toxicity was reported. The multivariable logistic regression suggests tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Also, it supports a positive effect on lethality rate of the use of corticosteroids. Conclusions: Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Such result support the use of tocilizumab while waiting for ongoing phase 3 trials.","type":"Research","database":"MedRxiv","created":"2020-10-12"},{"id":397,"name":"Vaccines and Drug Therapeutics to Lock Down Novel Coronavirus Disease 2019 (COVID-19): A Systematic Review of Clinical Trials","author":"Akshaya S. Bhagavathula, Wafa A. Aldhaleei, Alessandro Rovetta, Jamal Rahmani","doi":"10.7759\/cureus.8342","abstract":"The ongoing novel coronavirus disease 2019 (COVID-19) pandemic has been responsible for millions of infections and hundreds of thousands of deaths. To date, there is no approved targeted treatment, and many investigational therapeutic agents and vaccine candidates are being considered for the treatment of COVID-19. To extract and summarize information on potential vaccines and therapeutic agents against COVID-19 at different stages of clinical trials from January to March 2020, we reviewed major clinical trial databases such as ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), and other primary registries between January and March 15, 2020. Interventional studies at different phases under the COVID-19 pipeline were included. A total of 249 clinical trials were identified between January to March 15, 2020. After filtering observational studies (194 studies), a total of 56 interventional trials were considered. The majority of clinical trials have been conducted on chloroquine (n=10) and traditional Chinese medications (TCMs; n=10), followed by antivirals (n=8), anti-inflammatory\/immunosuppressants (n=9), cellular therapies (n=4), combinations of different antivirals therapies (n=3), antibacterial (n=1), and other therapies (n=5). Five vaccines are under phase I, and there are a couple of phase III trials on the Bacillus Calmette-Gu\u00e9rin (BCG) vaccine under investigation among healthcare workers. Many novel compounds and vaccines against COVID-19 are currently under investigation. Some candidates have been tested for other viral infections and are listed for clinical trials against the COVID-19 pipeline. Currently, there are no effective specific antivirals or drug combinations available for the treatment of COVID-19.","type":"Review","database":"PubMed","created":"2020-10-06"},{"id":396,"name":"Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations","author":"Mohamed Hagar, Hoda A. Ahmed, Ghadah Aljohani, Omaima A. Alhaddad","doi":"10.3390\/ijms21113922","abstract":"The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease Mpro, because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2\u2032-Fluoro-2\u2032-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (\u22127.77 Kcal\/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity \u22126.06 and \u22124.96 Kcal\/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.","type":"Research","database":"PubMed","created":"2020-10-06"},{"id":395,"name":"A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19","author":"D.R. Boulware, M.F. Pullen, A.S. Bangdiwala, K.A. Pastick, S.M. Lofgren, E.C. Okafor, C.P. Skipper, A.A. Nascene, M.R. Nicol, M. Abassi, N.W. Engen, M.P. Cheng, D. LaBar, S.A. Lother, L.J. MacKenzie, G. Drobot, N. Marten, R. Zarychanski, L.E. Kelly, I.S. Schwartz, E.G. McDonald, R. Rajasingham, T.C. Lee, and K.H. Hullsiek","doi":"10.1056\/NEJMoa2016638","abstract":"BACKGROUND\r\nCoronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the\r\nstandard of care is observation and quarantine. Whether hydroxychloroquine can\r\nprevent symptomatic infection after SARS-CoV-2 exposure is unknown.\r\nMETHODS\r\nWe conducted a randomized, double-blind, placebo-controlled trial across the\r\nUnited States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes\r\nwhile wearing neither a face mask nor an eye shield (high-risk exposure) or while\r\nwearing a face mask but no eye shield (moderate-risk exposure). Within 4 days\r\nafter exposure, we randomly assigned participants to receive either placebo or\r\nhydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg\r\ndaily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.\r\nRESULTS\r\nWe enrolled 821 asymptomatic participants. Overall, 87.6% of the participants\r\n(719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The\r\nincidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those\r\nreceiving placebo (58 of 407 [14.3%]); the absolute difference was \u22122.4 percentage\r\npoints (95% confidence interval, \u22127.0 to 2.2; P=0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious\r\nadverse reactions were reported.\r\nCONCLUSIONS\r\nAfter high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not\r\nprevent illness compatible with Covid-19 or confirmed infection when used as\r\npostexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki\r\nand Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.)","type":"Research","database":"PubMed","created":"2020-10-06"},{"id":394,"name":"Druggability for COVID19 \u2013 in Silico Discovery of Potential Drug Compounds Against Nucleocapsid (N) Protein of SARS-CoV-2","author":"Manisha Ray, Saurav Sarkar, Surya Narayan Rath","doi":"10.5808\/GI.2020.18.4.e43","abstract":"The coronavirus disease 2019 is a contagious disease and had caused havoc throughout the world by creating widespread mortality and morbidity. The unavailability of vaccines and proper antiviral drugs encourages the researchers to identify potential antiviral drugs to be used against the virus. The presence of RNA binding domain in the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be a potential drug target, which serves multiple critical functions during the viral life cycle, especially the viral replication. Since vaccine development might take some time, the identification of a drug compound targeting viral replication might offer a solution for treatment. The study analyzed the phylogenetic relationship of N protein sequence divergence with other 49 coronavirus species and also identified the conserved regions according to protein families through conserved domain search. Good structural binding affinities of a few natural and\/or synthetic phytocompounds or drugs against N protein were determined using the molecular docking approaches. The analyzed compounds presented the higher numbers of hydrogen bonds of selected chemicals supporting the drug-ability of these compounds. Among them, the established antiviral drug glycyrrhizic acid and the phytochemical theaflavin can be considered as possible drug compounds against target N protein of SARS-CoV-2 as they showed lower binding affinities. The findings of this study might lead to the development of a drug for the SARS-CoV-2 mediated disease and offer solution to treatment of SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2020-09-21"},{"id":393,"name":"Rapid systematic review on clinical evidence of chloroquine and hydroxychloroquine in COVID-19: critical assessment and recommendation for future clinical trials","author":"Yitong Wang, Shuyao Liang, Tingting Qiu, Ru Han, Monique Dabbous, Anna Nowotarska, Mondher Toumi","doi":"10.1101\/2020.06.01.20118901","abstract":"Purpose: This study aims to critically assess the published studies of Chloroquine (CQ) and\r\nhydroxychloroquine (HCQ) for the treatment of COVID-19 and provide recommendations for future\r\nclinical trials for the COVID-19 pandemic.\r\n\r\nMethod: A rapid systematic review was conducted by searching the PubMed, Embase, and China\r\nNational Knowledge Infrastructure databases on April 13, 2020. Three clinical trial registry platforms,\r\nincluding ClinicalTrials.gov, the EU Clinical Trials Register, and the Chinese Clinical Trial Register were\r\nalso complementarily searched.\r\n\r\nResults: A total of 10 clinical studies were identified, including 3 randomized controlled trials (RCTs), 1\r\ncomparative nonrandomized trial, 5 single-arm trials, and 1 interim analysis. The heterogeneity among\r\nstudies of the baseline disease severity and reported endpoints made a pooled analysis impossible. CQ and\r\nHCQ (with or without azithromycin) showed significant therapeutic benefit in terms of virologic clearance\r\nrate, improvement in symptoms and imaging findings, time to clinical recovery, and length of hospital\r\nstay in 1 RCT, 4 single-arm trials, and the interim analysis, whereas no treatment benefit of CQ or HCQ\r\nwas observed in the remaining 4 studies. Limitations of the included studies ranged from small sample\r\nsize, to insufficient information concerning baseline patient characteristics, to potential for selection bias\r\nwithout detailing the rationale for exclusion, and presence of confounding factors.\r\n\r\nConclusion: Based on the studies evaluated, there still lacked solid evidence supporting the efficacy and\r\nsafety of HCQ and CQ as a treatment for COVID-19 with or without azithromycin. This emphasized the\r\nimportance of robust RCTs investing HCQ\/CQ to address the evidence uncertainties. ","type":"Review","database":"MedRxiv","created":"2020-09-21"},{"id":392,"name":"Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein \u2013 an in silico insight into the comparative efficacy of repurposing antiviral drugs","author":"Muhammad Amin, Ghazanfar Abbas","doi":"10.1080\/07391102.2020.1775703","abstract":"Recent outbreak of novel Coronavirus disease () pandemic around the world is associated with severe acute respiratory syndrome. The death toll associated with the pandemic is increasing day by day. SARS-CoV-2 is an enveloped virus and its N terminal domain (NTD) of Nucleocapsid protein (N protein) binds to the viral (+) sense RNA and results in virus ribonucleoprotien complex, essential for the virus replication. The N protein is composed of a serine-rich linker region sandwiched between NTD and C terminal (CTD). These terminals play a role in viral entry and its processing post entry. The NTD of SARS-CoV-2 N protein forms orthorhombic crystals and binds to the viral genome. Therefore, there is always a quest to target RNA binding domain of nucleocapsid phosphoprotein (NTD-N-protein which in turn may help in controlling diseases caused by SARS-CoV-2 in humans. The role of Chloroquine and Hydroxychloroquine as potential treatments for is still under debate globally because of some side effects associated with it. This study involves the In silico interactions of Chloroquine and Hydroxychloroquine with the NTD-N-protein of SARS-CoV-2. With the help of various computational methods, we have explored the potential role of both of these antiviral drugs for the treatment of patients by comparing the efficacy of both of the drugs to bind to NTD-N-protein. In our research Hydroxychloroquine exhibited potential inhibitory effects of NTD-N-protein with binding energy \u22127.28\u2009kcal\/mol than Chloroquine (\u22126.30\u2009kcal\/mol) at SARS-CoV-2 receptor recognition of susceptible cells. The outcomes of this research strongly appeal for in vivo trials of Hydroxychloroquine for the patients infected with . Furthermore, the recommended doses of Hydroxychloroquine may reduce the chances of catching to the healthcare workers and staff who are in contact with or delivering direct care to coronavirus patients as long as they have not been diagnosed with . We further hypothesize that the comparative NTD-N-protein -drug docking interactions may help to understand the comparative efficacy of other candidate repurposing drugs until discovery of a proper vaccine.","type":"Research","database":"PubMed","created":"2020-09-21"},{"id":391,"name":"Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition","author":"Aleix Gimeno, J\u00falia Mestres-Truyol, Mar\u00eda Jos\u00e9 Ojeda-Montes, Guillem Macip, Bryan Saldivar-Espinoza, Adri\u00e0 Cereto-Massagu\u00e9, Gerard Pujadas, Santiago Garcia-Vallv\u00e9","doi":"10.3390\/ijms21113793","abstract":"Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread\r\nworldwide, the scientific community has been under pressure to react and make progress in the\r\ndevelopment of an effective treatment against the virus responsible for the disease. Here, we implement\r\nan original virtual screening (VS) protocol for repositioning approved drugs in order to predict which\r\nof them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given\r\nits essential role in the virus\u2019 replication. Two different libraries of approved drugs were docked\r\nagainst the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high\r\naffinity binding modes predicted simultaneously by the three docking programs were considered to\r\ncorrespond to bioactive poses. In this way, we took advantage of the three sampling algorithms to\r\ngenerate hypothetic binding modes without relying on a single scoring function to rank the results.\r\nSeven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel,\r\nCarprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen\r\nand Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show\r\n3.97 and 11.90% M-pro inhibition at 50 \u00b5M, respectively.","type":"Research","database":"PubMed","created":"2020-09-21"},{"id":390,"name":"Remdesivir-bound and ligand-free simulations reveal the probable mechanism of inhibiting the RNA dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2","author":"Shruti Koulgi, Vinod Jani, Mallikarjunachari V. N. Uppuladinne, Uddhavesh Sonavane, Rajendra Joshi","doi":"10.1039\/d0ra04743k","abstract":"The efforts towards developing a potential drug against the current global pandemic, COVID-19, have increased in the past few months. Drug development strategies to target the RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are being tried worldwide. The gene encoding this protein, is known to be conserved amongst positive strand RNA viruses. This enables an avenue to repurpose the drugs designed against earlier reported inhibitors of RdRP. One such strong inhibitor is remdesivir which has been used against EBOLA infections. The binding of remdesivir to RdRP of SARS-CoV-2 has been studied using the classical molecular dynamics and ensemble docking approach. A comparative study of the simulations of RdRP in the apo and remdesivir-bound form revealed blocking of the template entry site in the presence of remdesivir. The conformation changes leading to this event were captured through principal component analysis. The conformational and thermodynamic parameters supported the experimental information available on the involvement of crucial arginine, serine and aspartate residues belonging to the conserved motifs in RdRP functioning. The catalytic site comprising of SER 759, ASP 760, and ASP 761 (SDD) was observed to form strong contacts with remdesivir. The significantly strong interactions of these residues with remdesivir may infer the latter's binding similar to the normal nucleotides thereby remaining unidentified by the exonuclease activity of RdRP. The ensemble docking of remdesivir too, comprehended the involvement of similar residues in interaction with the inhibitor. This information on crucial interactions between conserved residues of RdRP with remdesivir through in silico approaches may be useful in designing inhibitors.","type":"Research","database":"ChemRxiv","created":"2020-09-21"},{"id":389,"name":"Profiling Molecular Simulations of SARS-CoV-2 Main Protease (Mpro) Binding to Repurposed Drugs Using Neural Network Force Fields","author":"Aayush Gupta","doi":"10.26434\/chemrxiv.12376094.v1","abstract":"With the current pandemic situation caused by a novel coronavirus disease (COVID-19), there is an urgent call to develop a working therapeutic against it. Efficient computations can minimize the efforts by identifying a subset of drugs that can potentially bind to the COVID-19 main protease or target protein (MPRO). The results of computations are accompanied by an evaluation of their accuracy, which depends on the details described by the model used. Neural network models trained on millions of points and with unmatched accuracies are the best approach to employ in this process. In this work, I first identified and described the interaction sites of the MPRO protein using a geometric deep learning model. Second, I conducted virtual screening (at one of the sites identified) on FDA-approved drugs and selected 91 drugs with the highest binding affinities (below -8.0 kcal\/mol). Then, I conducted 10 ns of molecular dynamics (MD) simulations using classical force fields and classified 37 drugs to be binding (including Lopinavir, Saquinavir, and Indinavir) based on the RMSD between MD-binding trajectories. To drastically improve the dynamics profile of the 37 selected drugs, I used the highly accurate neural network force field (ANI) method trained on coupled-cluster method (CCSD(T)\/CBS) data points and performed 1 ns of binding dynamics for each drug with the protein. Using this approach, 19 drugs were qualified based on their RMSD cutoffs, and based on free energy (ANI\/MM\/PBSA) computations, 7 of the drugs were rejected. The final selection of 12 drugs was validated based on an MD trajectory clustering approach where 11 of the 12 drugs (Targretin, Eltrombopag, Rifaximin, Deflazacort, Ergotamine, Doxazosin, Lastacaft, Rifampicin, Victrelis, Trajenta, Toposar, and Indinavir) were confirmed to exhibit binding. Further investigations were performed to study their interactions with the protein and an accurate 2D-interaction map was generated. These findings and mappings of drug-protein interactions are highly accurate and may be potentially used to guide rational drug discovery against COVID-19.","type":"Research","database":"ChemRxiv","created":"2020-09-21"},{"id":388,"name":"Identification of Drugs Targeting Multiple Viral and Human Proteins Using Computational Analysis for Repurposing Against COVID-19","author":"Sugandh Kumar, Pratima Kumari, Geetanjali Agnihotri, Preethy VijayKumar, Shaheerah Khan, Gulam Hussain Syed, Anshuman Dixit","doi":"10.26434\/chemrxiv.12366938.v1","abstract":"The SARS-CoV2 is a highly contagious pathogen that causes a respiratory disease named COVID-19. The COVID-19 was declared a pandemic by the WHO on 11th March 2020. It has affected about 5.38 million people globally (identified cases as on 24th May 2020), with an average lethality of ~3%. Unfortunately, there is no standard cure for the disease, although some drugs are under clinical trial. Thus, there is an urgent need of drugs for the treatment of COVID-19. The molecularly targeted therapies have proven their utility in various diseases such as HIV, SARS, and HCV. Therefore, a lot of efforts are being directed towards the identification of molecules that can be helpful in the management of COVID-19.\r\n\r\nIn the current studies, we have used state of the art bioinformatics techniques to screen the FDA approved drugs against thirteen SARS-CoV2 proteins in order to identify drugs for quick repurposing. The strategy was to identify potential drugs that can target multiple viral proteins simultaneously. Our strategy originates from the fact that individual viral proteins play specific role in multiple aspects of viral lifecycle such as attachment, entry, replication, morphogenesis and egress and targeting them simultaneously will have better inhibitory effect.\r\n\r\nAdditionally, we analyzed if the identified molecules can also affect the host proteins whose expression is differentially modulated during SARS-CoV2 infection. The differentially expressed genes (DEGs) were identified using analysis of NCBI-GEO data (GEO-ID: GSE-147507). A pathway and protein-protein interaction network analysis of the identified DEGs led to the identification of network hubs that may play important roles in SARS-CoV2 infection. Therefore, targeting such genes may also be a beneficial strategy to curb disease manifestation. We have identified 29 molecules that can bind to various SARS-CoV2 and human host proteins. We hope that this study will help researchers in the identification and repurposing of multipotent drugs, simultaneously targeting the several viral and host proteins, for the treatment of COVID-19.","type":"Research","database":"ChemRxiv","created":"2020-09-21"},{"id":387,"name":"Molecular Mechanism of Clinically Oriented Drug Famotidine with the Identified Potential Target of SARS-CoV-2","author":"Parth Sarthi Sen Gupta, Satyaranjan Biswal, Dipankar Singha, Malay Kumar Rana","doi":"10.26434\/chemrxiv.12382265.v1","abstract":"Due to the current pandemic nature, severity, and rapid spread of COVID-19, there is eminent need to identify potential therapeutics to inhibit the novel coronavirus. In the quest, scientists from the USA had reported that the use of Famotidine in patients was associated with improved clinical outcomes and a reduced risk of intubation or death from COVID-19. However, the exact mode of action, the binding mechanism, and precise COVID-19 molecular target with which Famotidine interacts are yet to be ascertained. Here, 12 different COVID-19 protein targets have been screened against Famotidine employing molecular docking and molecular dynamics simulation. This reveals, among all the targets, the Papain-like protease (PLpro) as the potential target having the strongest affinity to Famotidine estimated to be of -7.9 kcal\/mol with three hydrogen bonds. Tyrosine residue in the 268th position in the binding site seems to be very crucial for the stability of the PLpro-Famotidine complex, giving rise to multiple interactions such as hydrogen bonding as well as \u03c0-Sulfur. While the post-molecular dynamics (MD) analyses such as the root-mean-square deviation (RMSD) and fluctuation (RMSF), the radius of gyration (Rg), and the principal component analysis (PCA) affirm the stability of the complex providing an insight into the binding mechanism, the identification of a valid target PLpro of SARS-COV-2 for Famotidine would help understand its action, further development, and experimental exploration.","type":"Research","database":"ChemRxiv","created":"2020-09-21"},{"id":386,"name":"Probing antiviral drugs against SARS-CoV-2 through virus-drug association prediction based on the KATZ method","author":"Liqian Zhou, Juanjuan Wang, Guangyi Liu, Qingqing Lu, Ruyi Dong, Geng Tian, Jialiang Yang, Lihong Penga","doi":"10.1016\/j.ygeno.2020.07.044","abstract":"It is urgent to find an effective antiviral drug against SARS-CoV-2. In this study, 96 virus-drug associations (VDAs) from 12 viruses including SARS-CoV-2 and similar viruses and 78 small molecules are selected. Complete genomic sequence similarity of viruses and chemical structure similarity of drugs are then computed. A KATZ-based VDA prediction method (VDA-KATZ) is developed to infer possible drugs associated with SARS-CoV-2. VDA-KATZ obtained the best AUCs of 0.8803 when the walking length is 2. The predicted top 3 antiviral drugs against SARS-CoV-2 are remdesivir, oseltamivir, and zanamivir. Molecular docking is conducted between the predicted top 10 drugs and the virus spike protein\/human ACE2. The results showed that the above 3 chemical agents have higher molecular binding energies with ACE2. For the first time, we found that zidovudine may be effective clues of treatment of COVID-19. We hope that our predicted drugs could help to prevent the spreading of COVID.","type":"Research","database":"PubMed","created":"2020-09-09"},{"id":385,"name":"Clinical trial to test the efficacy of melatonin in COVID\u201019","author":"Dario Acu\u00f1a\u2010Castroviejo, Germaine Escames, Juan C. Figueira,  Pedro de la Oliva,  Alberto M. Borobia,  Carlos Acu\u00f1a\u2010Fern\u00e1ndez","doi":"10.1111\/jpi.12683","abstract":"The pharmacological properties of melatonin are well known. However, there is noticeable the lack of clinical trials that confirm the efficacy, security, absence of side effects in the short and long term, and the effective doses of melatonin. This point is especially important in diseases with high morbidity and mortality including COVID\u201019. There is not treatment for COVID\u201019, and several anti\u2010inflammatory and antiviral molecules are being tested, and different vaccines are in preparation. Although the SARS\u2010CoV\u20102 pandemic is apparently improving, it is expected new resurges next fall. Thus, looking for an effective treatment of COVID\u201019 is mandatory. Melatonin has significant anti\u2010inflammatory, antioxidant, and mitochondrial protective effects, and its efficacy has been demonstrated in multiple experimental models of disease and in a clinical trial in sepsis. Because COVID\u201019 courses with a severe septic response, multiple reviews proposing melatonin as a treatment for COVID\u201019 have been published. Nevertheless, there is a lack of experimental and clinical data on the use of melatonin on SARS\u2010CoV\u20102 infection. Accordingly, we designed a clinical trial with an injectable formulation of melatonin for intravenous perfusion in ICU patients suffering from COVID\u201019 that has been just approved by the Spanish Agency of Medicines and Medical Devices (AEMPS). The trial will allow by the first time understand the doses and efficacy of melatonin against COVID\u201019.","type":"Comment","database":"PubMed","created":"2020-09-09"},{"id":384,"name":"AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II\/III Multicenter Randomized Clinical Trial","author":"Andrey A Ivashchenko, Kirill A Dmitriev, Natalia V Vostokova, Valeria N Azarova, Andrew A Blinow, Alina N Egorova, Ivan G Gordeev, Alexey P Ilin, Ruben N Karapetian, Dmitry V Kravchenko, Nikita V Lomakin, Elena A Merkulova, Natalia A Papazova, Elena P Pavlikova, Nikolay P Savchuk, Elena N Simakina, Tagir A Sitdekov, Elena A Smolyarchuk, Elena G Tikhomolova, Elena V Yakubova, Alexandre V Ivachtchenko","doi":"10.1093\/cid\/ciaa1176","abstract":"In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to RNA polymerase inhibitor AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. In the pilot stage of Phase II\/III clinical trial, AVIFAVIR enabled SARS-CoV-2 viral clearance in 62.5% of patients within 4 days, and was safe and well-tolerated.","type":"Research","database":"PubMed","created":"2020-09-09"},{"id":383,"name":"Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach","author":"Shweta Choudhary, Yashpal S. Malik, Shailly Tomar","doi":"10.3389\/fimmu.2020.01664","abstract":"The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.","type":"Research","database":"PubMed","created":"2020-09-09"},{"id":382,"name":"Identification of potential drug candidates to combat COVID-19: a structural study using the main protease (mpro) of SARS-CoV-2","author":"Pradeep Sharma , Viswanathan Vijayan , Pradeep Pant , Mohita Sharma , Naval Vikram , Punit Kaur , T. P. Singh & Sujata Sharma","doi":"10.1080\/07391102.2020.1798286","abstract":"The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19 has become a global pandemic that is spreading rapidly and has caused a global health emergency. Hence, there is an urgent need of the hour to discover effective drugs to control the pandemic caused by this virus. Under such conditions, it would be imperative to repurpose already known drugs which could be a quick and effective alternative to discovering new drugs. The main protease (Mpro) of SARS-COV-2 is an attractive drug target because of its essential role in the processing of the majority of the non- structural proteins which are translated from viral RNA. Herein, we report the high-throughput virtual screening and molecular docking studies to search for the best potential inhibitors against Mpro from FDA approved drugs available in the ZINC database as well as the natural compounds from the Specs database. Our studies have identified six potential inhibitors of Mpro enzyme, out of which four are commercially available FDA approved drugs (Cobicistat, Iopromide, Cangrelor, and Fortovase) and two are from Specs database of natural compounds (Hopeaphenol and Cyclosieversiodide-A). While Cobicistat and Fortovase are known as HIV drugs, Iopromide is a contrast agent and Cangrelor is an anti-platelet drug. Furthermore, molecular dynamic (MD) simulations using GROMACS were performed to calculate the stability of the top-ranked compounds in the active site of Mpro. After extensive com- putational studies, we propose that Cobicistat and Hopeaphenol show potential to be excellent drugs that can form the basis of treating COVID-19 disease.","type":"Research","database":"PubMed","created":"2020-09-09"},{"id":381,"name":"Current status and strategic possibilities on potential use of combinational drug therapy against COVID-19 caused by SARS-CoV-2","author":"Arif Jamal Siddiqui , Sadaf Jahan , Syed Amir Ashraf , Mousa Alreshidi , Mohammad Saquib Ashraf , Mitesh Patel , Mejdi Snoussi , Ritu Singh, Mohd Adnan","doi":"10.1080\/07391102.2020.1802345","abstract":"The spread of new coronavirus infection starting December 2019 as novel SARS-CoV-2, identified as the causing agent of COVID-19, has affected all over the world and been declared as pandemic. Approximately, more than 8,807,398 confirmed cases of COVID-19 infection and 464,483 deaths have been reported globally till the end of 21 June 2020. Until now, there is no specific drug therapy or vaccine available for the treatment of COVID-19. However, some potential antimalarial drugs like hydroxychloroquine and azithromycin, antifilarial drug ivermectin and antiviral drugs have been tested by  many  research  groups  worldwide  for  their  possible  effect  against  the  COVID-19. Hydroxychloroquine and ivermectin have been identified to act by creating the acidic condition in cells and inhibiting the importin (IMPa\/b1) mediated viral import. There is a possibility that some other antimalarial drugs\/antibiotics in combination with immunomodulators may help in combatting this pandemic disease. Therefore, this review focuses on the current use of various drugs as single agents (hydroxychloroquine, ivermectin, azithromycin, favipiravir, remdesivir, umifenovir, teicoplanin, nitazoxa- nide, doxycycline, and dexamethasone) or in combinations with immunomodulators additionally. Furthermore, possible mode of action, efficacy and current stage of clinical trials of various drug com- binations against COVID-19 disease has also been discussed in detail. ","type":"Review","database":"PubMed","created":"2020-09-09"},{"id":380,"name":"Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19","author":"Yuan Huang, Chan Yang, Xin-feng Xu, Wei Xu, Shu-wen Liu","doi":"10.1038\/s41401-020-0485-4","abstract":"Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.","type":"Review","database":"PubMed","created":"2020-09-09"},{"id":379,"name":"Molecular docking, molecular dynamics simulations and reactivity, studies on approved drugs library targeting ACE2 and SARS-CoV-2 binding with ACE2","author":"Hadjer Khelfaoui , Dalal Harkati & Basil A. Saleh","doi":"10.1080\/07391102.2020.1803967","abstract":"The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 which infected millions confirmed cases and hundreds of thousands death cases around the world so far. Molecular docking combined with molecular dynamics is one of the most important tools of drug discovery and drug design, which it used to examine the type of binding between the ligand and its protein enzyme. Global reactivity has important properties, which enable chemists to understand the chemical reactivity and kinetic stability of compounds. In this study, molecular docking and reactivity were applied for eighteen drugs, which are similar in structure to chloroquine and hydroxychloroquine, the potential inhibitors to angiotensin-converting enzyme (ACE2). Those drugs were selected from DrugBank. The reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2 and [SARS-CoV-2\/ACE2] complex receptor in two active sites to find a ligand, which may inhibit COVID-19. The results obtained from this study showed that Ramipril, Delapril and Lisinopril could bind with ACE2 receptor and [SARS-CoV-2\/ACE2] complex better than chloroquine and hydroxychloroquine. This new understanding should help to improve predictions of the impact of such alternatives on COVID-19.","type":"Research","database":"PubMed","created":"2020-09-02"},{"id":378,"name":"SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial","author":"Fang Zheng, Yanwen Zhou, Zhiguo Zhou, Fei Yeh, Baoying Huang, Yaxiong Huang, Jing Ma, Qi Zuo, Xin Tan, Jun Xie, Peihua Niu, Wenlong Wang, Yun Xu, Feng Peng , Ning Zhou, Chunlin Cai, Wei Tang, Xinqiang Xiao, Yi Li, Zhiguang Zhou, Yongfang Jiang, Yuanlin Xie, Wenjie Tan, Guozhong Gong","doi":"10.1016\/j.ijid.2020.07.053","abstract":"Background\r\nThe antiviral effects of Novaferon, a potent antiviral protein drug, on COVID-19 was evaluated in the laboratory, and in a randomized, open-label, parallel-group trial.\r\nMethods\r\nIn the laboratory, Novaferon's inhibition of viral replication in cells infected with SARS-CoV-2, and prevention of SARS-CoV-2 entry into healthy cells was determined. Antiviral effects of Novaferon in COVID-19 patients with treatment of Novaferon, Novaferon plus Lopinavir\/Ritonavir, or Lopinavir\/Ritonavir were evaluated. The primary endpoint was the SARS-CoV-2 clearance rates on day six of treatment, and the secondary endpoint was the time to SARS-CoV-2 clearance.\r\nResults\r\nNovaferon inhibited viral replication (EC50\u2005=\u20051.02\u2005ng\/ml), and prevented viral infection (EC50\u2005=\u20050.10\u2005ng\/ml). Results from the 89 enrolled COVID-19 patients showed that both Novaferon and Novaferon plus Lopinavir\/Ritonavir groups had significantly higher viral clearance rates on day six than Lopinavir\/Ritonavir group (50.0% vs. 24.1%, p\u2005=\u20050.0400, and 60.0% vs. 24.1%, p\u2005=\u20050.0053). The median time to viral clearance was six days, six days, and nine days for three groups, respectively, a 3-day reduction in both the Novaferon and Novaferon plus Lopinavir\/Ritonavir groups compared with the Lopinavir\/Ritonavir group.\r\nConclusions\r\nNovaferon exhibited anti-SARS-CoV-2 effects in vitro and in COVID-19 patients. These data justify further evaluation of Novaferon.\r\nTrial registration number\r\nNumber ChiCTR2000029496 at the Chinese Clinical Trial Registry (http:\/\/www.chictr.org.cn\/).","type":"Research","database":"PubMed","created":"2020-09-02"},{"id":377,"name":"Pyronaridine and artesunate are potential antiviral drugs against COVID-19 and influenza","author":"Joon-Yong Bae, Gee Eun Lee, Heedo Park, Juyoung Cho, Yung-Eui Kim, Joo-Yeon Lee, Chung Ju, Won-Ki Kim, Jin Il Kim, Man-Seong Park","doi":"10.1101\/2020.07.28.225102","abstract":"Since the first human case was reported in Wuhan Province, China in December 2019, SARS-CoV-2 has caused millions of human infections in more than 200 countries worldwide with an approximately 4.01% case-fatality rate (as of 27 July, 2020; based on a WHO situation report), and COVID-19 pandemic has paralyzed our global community. Even though a few candidate drugs, such as remdesivir (a broad antiviral prodrug) and hydroxychloroquine, have been investigated in human clinical trials, their therapeutic efficacy needs to be clarified further to be used to treat COVID-19 patients. Here we show that pyronaridine and artesunate, which are the chemical components of anti-malarial drug Pyramax\u00ae, exhibit antiviral activity against SARS-CoV-2 and influenza viruses. In human lung epithelial (Calu-3) cells, pyronaridine and artesunate were highly effective against SARS-CoV-2 while hydroxychloroquine did not show any effect at concentrations of less than 100 \u03bcM. In viral growth kinetics, both pyronaridine and artesunate inhibited the growth of SARS-CoV-2 and seasonal influenza A virus in Calu-3 cells. Taken together, we suggest that artesunate and pyronaridine might be effective drug candidates for use in human patients with COVID-19 and\/or influenza, which may co-circulate during this coming winter season.","type":"Research","database":"BioRxiv","created":"2020-09-02"},{"id":376,"name":"Effect and safety of combination of interferon alpha-2b and gamma or interferon alpha-2b for negativization of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial.","author":"Esquivel-Moynelo Idelsis, Perez-Escribano Jesus, Duncan-Robert Yaquelin, Vazquez-Blonquist Dania, Bequet-Romero Monica, Baez-Rodriguez Lisandra, Castro-Rios Jesus, Cobas Cervantes Lisbeth, Page-Calvet Ernesto, Travieso-Perez Saily, Martinez-Suarez Claudia, Campa-Legra Ivan, Fernandez-Masso Julio Raul, Camacho-Rodriguez Hamlet, Diaz-Galvez Marisol, Sin-Mayor Adriana, Garcia-Sanchez Maura, Martinez-Martin Sara Maria, Alonso-Valdes Marel, Hernandez-Bernal Francisco, Nodarse-Cuni Hugo, Bello-Garcia ","doi":"10.1101\/2020.07.29.20164251","abstract":"Abstract Objectives: IFN-alpha2b and IFN-gamma combination has demonstrated favorable pharmacodynamics for genes underlying antiviral activity which might be involved in the defense of the organism from a SARS-CoV-2 infection. Considering this we conducted a randomized controlled clinical trial for efficacy and safety evaluation of subcutaneous IFN-alpha2b and IFN-gamma administration in patients positive to SARS-CoV-2. Methods: We enrolled 19-82 years-old inpatients at the Military Central Hospital Luis Diaz Soto, Havana, Cuba. They were hospitalized after confirmed diagnosis for SARS-CoV-2 RNA by real-time reverse transcription polymerase chain reaction. Patients were randomly assigned in a 1:1 ratio to receive either, subcutaneous treatment with a co-lyophilized combination of 3.0 MIU IFN-alpha2b and 0.5 MIU IFN-gamma (HeberFERON, CIGB, Havana, Cuba), twice a week for two weeks, or thrice a week intramuscular injection of 3.0 MIU IFN-alpha2b (Heberon Alpha R, CIGB, Havana, Cuba). Additionally, all patients received lopinavir-ritonavir 200\/50 mg every 12 h and chloroquine 250 mg every 12 h (standard of care). The primary endpoints were the time to negativization of viral RNA and the time to progression to severe COVID-19, from the start of treatment. The protocol was approved by the Ethics Committee on Clinical Investigation from the Hospital and the Center for the State Control of Medicines, Equipment and Medical Devices in Cuba. Informed consent was obtained from each participant. Results: A total of 79 patients with laboratory-confirmed SARS-CoV-2 infection, including symptomatic or asymptomatic conditions, fulfilled the inclusion criteria and underwent randomization. Thirty-three subjects were assigned to the HeberFERON group, and 33 to the Heberon Alpha R group. Sixty-three patients were analyzed for viral negativization, of them 78.6% in the HeberFERON group negativized the virus after 4 days of treatment versus 40.6% of patients in the Heberon Alpha R groups (p=0.004). Time to reach the negativization of the SARS-CoV-2 measured by RT-PCR in real time was of 3.0 and 5.0 days for the HeberFERON and Heberon Alpha R groups, respectively. A significant improvement in the reduction of time for negativization was attributable to HeberFERON (p=0.0027, Log-rank test) with a Hazard Ratio of 3.2 and 95% CI of 1.529 to 6.948, as compared to Heberon Alpha R treated group. Worsening of respiratory symptoms was detected in two (6.6%) and one (3.3%) patients in HeberFERON and IFN-alpha2b groups, respectively. None of the subjects transit to severe COVID-19 during the study or the epidemiological follow-up for 21 more days. RT-PCR on day 14 after the start of the treatment was negative to SARS-CoV-2 in 100% and 91% of patients of the combination of IFNs and IFN-alpha2b, respectively. Negativization for HeberFERON treated patients was related to a significant increase in lymphocytes counts and an also significant reduction in CRP as early as 7 days after commencing the therapeutic schedule. All the patients in both cohorts recover by day 14 and were in asymptomatic condition and laboratory parameters return to normal values by day 14 after treatment initiation. Adverse events were identified in 31.5% of patients, 28.5% in the control group, and 34.4% in the HeberFERON group, and the most frequent were headaches (17.4%). Conclusions: In a cohort of 63 hospitalized patients between 19 to 82 years-old with positive SARS-CoV-2, HeberFERON significantly negativized the virus on day 4 of treatment when comparing with IFN-alpha2b. Heberon Alpha R also showed efficacy for the treatment of the viral infection. Both treatments were safe and positively impact on the resolution of the symptoms. None of the patients developed severe COVID-19. Key words: COVID-19, treatment, drug, virus negativization, antiviral, interferon combination, SARS CoV-2.","type":"Research","database":"MedRxiv","created":"2020-09-01"},{"id":375,"name":"Computational Identification of Drug Lead Compounds for COVID-19 from Moringa Oleifera","author":"Dr. Divya Shaji","doi":"10.26434\/chemrxiv.12535913.v1","abstract":"COVID-19 which is caused by the virus SARS-CoV-2, has now been declared a global pandemic by the World Health Organization. At present, no specific vaccines or drugs are available to treat COVID-19. Therefore, there is an urgent need for the identification of novel drug lead compounds\r\nto treat COVID-19. The SARS-CoV-2 main protease (Mpro also known as 3CLpro) and RNA-dependent RNA polymerase (RdRp also known as nsp12) are the best-characterized drug targets among corona viruses. In order to discover the natural lead compounds for SARS-CoV-2, we\r\nperformed molecular docking with the compounds from Moringa Oleifera that target the Mpro and RdRp. The molecular docking studies were carried out using AutoDock Vina through PyRx. Drug-likeness property of the selected compounds was checked by applying the \u2018Lipinski\u2019s rule of five\u2019 using Swiss ADME. The top four compounds with most favourable binding affinity were selected for each of the targets. The results indicated that the compounds kaempferol, pterygospermin, morphine and quercetin exhibited best binding energy towards Mpro and RdRp. This study suggests that these natural compounds could be promising candidates for further evaluation of COVID-19 prevention.","type":"Research","database":"ChemRxiv","created":"2020-07-28"},{"id":374,"name":"Review of trials currently testing treatment and prevention of COVID-19.","author":"P. C. Fragkou, D. Belhadi, N. Peiffer-Smadja, C. D. Moschopoulos, F. X. Lescure, H. Janocha, E. Karofylakis, Y. Yazdanpanah, F. Mentr\u00e9, C. Skevaki, C. Laou\u00e9nan, S. Tsiodras","doi":"10.1016\/j.cmi.2020.05.019","abstract":"\r\n\r\nBackground: As COVID-19 cases continue to rise globally, evidence from large randomized controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are being undertaken all over the world.\r\n\r\nObjectives: We summarized all registered clinical trials examining treatment and prevention options for COVID-19. Additionally, we evaluated the quality of the retrieved studies.\r\n\r\nData sources: Clinicaltrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched.\r\n\r\nStudy eligibility criteria: Registered clinical trials examining treatment and\/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. We excluded withdrawn or cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19.\r\n\r\nParticipants and interventions: No restrictions in terms of participants' age and medical background or type of intervention were enforced.\r\n\r\nMethods: The registries were searched using the term 'coronavirus' or 'COVID-19' from their inception until 26 March 2020. Additional manual search of the registries was also performed. Eligible studies were summarized and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing traditional Chinese medicine.\r\n\r\nResults: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and three studies examining both were retrieved. Finally, 214 studies were methodologically reviewed. Interventional treatment studies were mostly randomized (n = 150\/198, 76%) and open label (n = 73\/198, 37%) with a median number of planned inclusions of 90 (interquartile range 40-200). Major categories of interventions that are currently being investigated are discussed.\r\n\r\nConclusions: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarized data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment.\r\n\r\nKeywords: Anti-inflammatory; Antivirals; COVID-19; Clinical trials; Immunomodulators; Novel coronavirus; Pneumonia; Prevention; SARS-CoV-2; Treatment. ","type":"Review","database":"PubMed","created":"2020-07-16"},{"id":373,"name":"Mass Drug Administration and Worms Experience in Africa: Envisage Repurposing Ivermectin for SARS-COV-2","author":"Claire Njeri Wamae","doi":"10.4269\/ajtmh.20-0295","abstract":null,"type":"Comment","database":"PubMed","created":"2020-07-15"},{"id":372,"name":"Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol","author":"Hajira Dambha-Miller, View ORCID ProfileAli Albasri, View ORCID ProfileSam Hodgson, Chris Wilcox, Nazrul Islam, Shareen Khan, Paul Little, Simon J Griffin","doi":"10.1101\/2020.05.25.20100438","abstract":"Background: The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs which up- or down-regulate ACE2 expression are therefore of critical research interest as agents which might promote or reduce risk of COVID-19 infection in a susceptible population. Aim: To review evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2 and potentially affect COVID-19 infection. Design and setting: Systematic review of studies published in MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science from inception to April 1st 2020. Method: A systematic review will be conducted in line with PRISMA guidelines. Inclusion criteria will be: i) assess effect of drug exposure on ACE2 level; ii) drug is included in British National Formulary (BNF) and therefore available to prescribe in UK; iii) a control, placebo or sham group is included as comparator. Exclusion criteria will be: i) ACE2 measurement in utero; ii) ACE2 measurement in children under 18 years; iii) drug not in BNF; iv) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYRCLE risk of bias tool for animal studies. Results: Data will be reported in summary tables and narrative synthesis. Conclusion: This systematic review will identify drug therapies which may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.","type":"Review","database":"MedRxiv","created":"2020-07-09"},{"id":371,"name":"COVID\u2010SAFER : Deprescribing Guidance for Hydroxychloroquine Drug Interactions in Older Adults","author":"Sydney B. Ross, Marnie Goodwin Wilson, Louise Papillon-Ferland, Sarah Elsayed, Peter E. Wu, Kiran Battu, Sandra Porter, Babak Rashidi, Robyn Tamblyn, Louise Pilote, James Downar, Andre Bonnici, Allen Huang, Todd C. Lee, Emily G. McDonald","doi":"10.1111\/jgs.16623","abstract":"BACKGROUND\/OBJECTIVES\r\nSevere acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug\u2010drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking that would interact with hydroxychloroquine.\r\n\r\nMETHODS\r\nWe reanalyzed data from the cohort of patients 65\u2009years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug\u2010drug interactions with hydroxychloroquine that might exclude them from participation in a typical 2019 coronavirus disease (COVID\u201019) therapeutic trial. Next, we identified medications that were flagged by MedSafer as potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine.\r\n\r\nRESULTS\r\nThe cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these, 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and antidiabetic agents.\r\n\r\nCONCLUSION\r\nThe COVID\u201019 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID\u201019.","type":"Research","database":"PubMed","created":"2020-07-09"},{"id":370,"name":"Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19","author":"Anshuman Chandra,Vaishali Gurjar,Imteyaz Qamar,Nagendra Singh","doi":"10.1080\/07391102.2020.1775127","abstract":"SARS-CoV-2 is causative agent of COVID-19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID-19. Nonstructural protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID-19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia, respectively, were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250, and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be \u2013141\u2009\u00b1\u200911 and \u2013136\u2009\u00b1\u200916\u2009kJ\/mol, respectively. The IC50 were predicted to be 9.2\u2009\u00b5M and 30\u2009\u00b5M for Glisoxepide and Idarubicin, respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than to uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8\u00c52 by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19.","type":"Research","database":"PMC","created":"2020-07-02"},{"id":368,"name":"Repurposing approved drugs as inhibitors of SARS-CoV-2\u2009S-protein from molecular modeling and virtual screening","author":"Osmair Vital de Oliveira, Gerd B. Rocha, Andrew S. Paluch, Luciano T. Costa","doi":"10.1080\/07391102.2020.1772885","abstract":"Herein, molecular modeling techniques were used with the main goal to obtain candidates from a drug database as potential targets to be used against SARS-CoV-2. This novel coronavirus, responsible by the COVID-19 outbreak since the end of 2019, became a challenge since there is not vaccine for this disease. The first step in this investigation was to solvate the isolated S-protein in water for molecular dynamics (MD) simulation, being observed a transition from \u201cup\u201d to \u201cdown\u201d conformation of receptor-binding domain (RBD) of the S-protein with angle of 54.3 and 43.0 degrees, respectively. The RBD region was more exposed to the solvent and to the possible drugs due to its enhanced surface area. From the equilibrated MD structure, virtual screening by docking calculations were performed using a library contained 9091 FDA approved drugs. Among them, 24 best-scored ligands (14 traditional herbal isolate and 10 approved drugs) with the binding energy below \u20138.1\u2009kcal\/mol were selected as potential candidates to inhibit the SARS-CoV-2\u2009S-protein, preventing the human cell infection and their replication. For instance, the ivermectin drug (present in our list of promise candidates) was recently used successful to control viral replication in vitro. MD simulations were performed for the three best ligands@S-protein complexes and the binding energies were calculated using the MM\/PBSA approach. Overall, it is highlighted an important strategy, some key residues, and chemical groups which may be considered on clinical trials for COVID-19 outbreak. ","type":"Research","database":"PubMed","created":"2020-07-01"},{"id":367,"name":"COVID-19; Systematic and literature review of transmission, case definitions, clinical management and clinical trials","author":"Laura McArthur, DhanaSekaran Sakthivel, Ricardo Ataide, Felicia Chan, Jack S Richards, Charles A Narh","doi":"10.1101\/2020.05.14.20102475","abstract":"Background: SARS-CoV-2, the viral agent responsible for coronavirus disease 2019 (COVID-19) was identified in Wuhan, China at the end of December 2019. It rapidly spread to the rest of the world, and was declared a Public Health Emergency of International Concern on the 30th of January 2020. Our understanding of the virus, it is clinical manifestations and treatment options continues to evolve at an unparalleled pace. Objective: This review sought to summarise the key literature regarding transmission, case definitions, clinical management and trials, and performed a systematic review of reported clinical data on COVID-19. Synthesis methods: Two reviewers selected all the literature independently, and extracted information according to pre-defined topics. Results: COVID-19 is pandemic with ~4 million cases and 270,000 deaths in 210 countries as of 8 May 2020. Our review of reports showed that SARS-CoV-2 was mainly transmitted via inhalation of respiratory droplets containing the virus and had an incubation period of four to six days. The commonly reported symptoms were fever (80%) and cough (60%) across the spectrum of clinical disease - mild, moderate, severe and critical. Categorization of these cases for home care or hospital management need to be well defined considering the age of the patient and the presence of underlying co-morbidities. The case definitions we reviewed varied among affected countries, which could have contributed to the differences observed in the mean case fatality rates among continents: Oceania (1%), Asia (3%), Africa (4%), South America (5%), North America (6%) and Europe (10%). Asymptomatic cases, which constituted an estimated 80% of COVID-19 cases are a huge threat to control efforts. Conclusion: The presence of fever and cough may be sufficient to warrant a COVID-19 testing but using these symptoms in isolation will miss a proportion of cases. A clear definition of a COVID-19 case is important for managing, treating and tracking clinical illness. While several treatments are in development or in clinical trials for COVID-19, home care of mild\/moderate cases and hospital care for severe and critical cases remain the recommended management for the disease. Quarantine measures and social distancing can help control the spread of SARS-CoV-2.","type":"Review","database":"MedRxiv","created":"2020-07-01"},{"id":366,"name":"Systematic and Statistical Review of COVID19 Treatment Trials","author":"Juan Arturo Siordia Jr., Michael Bernaba, Kenji Yoshino, Abid Ulhaque, Sooraj Kumar, Mario Bernaba, Edward Bergin","doi":"10.1101\/2020.05.16.20102095","abstract":"Objective: The following systematic review and meta-analysis compiles the current data regarding human controlled COVID-19 treatment trials. Methods: An electronic search of the literature compiled studies pertaining to human controlled treatment trials with COVID-19. Medications assessed included lopinavir\/ritonavir, arbidol, hydroxychloroquine, favipiravir, and heparin. Statistical analyzes were performed for common viral clearance endpoints whenever possible. Results: Lopinavir\/ritonavir showed no significant effect on viral clearance for COVID-19 cases (OR 0.95 [95% CI 0.50-1.83]). Hydroxychloroquine also showed no significant effect on COVID-19 viral clearance rates (OR 2.16 [95% CI 0.80-5.84]). Arbidol showed no seven-day (OR 1.63 [95% CI 0.76-3.50]) or 14-day viral (OR 5.37 [95% CI 0.35-83.30]) clearance difference compared to lopinavir\/ritonavir. Review of literature showed no significant clinical improvement with lopinavir\/ritonavir, arbidol, hydroxychloroquine, or remdesivir. Favipiravir showed quicker symptom improvement compared to lopinavir\/ritonavir and arbidol. Heparin showed improvement with severe COVID-19 cases. Conclusion: Current medications do not show significant effect on COVID-19 viral clearance rates. Favipiravir shows favorable results compared to other tested medications. Heparin shows benefit for severe cases of COVID-19.","type":"Review","database":"MedRxiv","created":"2020-07-01"},{"id":365,"name":"Emergency Antiviral Drug Discovery During a Pandemic - a Case Study on the Application of Natural Compounds to Treat COVID-19","author":"Jianfeng Yu, Shengxi Shao, Bin Liu, Zhihao Wang, Yi-Zhou Jiang, Yunqing Li, Feng Chen, Bing Liu","doi":"10.26434\/chemrxiv.12307592.v1","abstract":"The spreading COVID-19 pandemic has brought the world to a halt in 2020. One of the major challenges is the lack of effective antiviral drugs. Drug and vaccine development typically takes years; a practical approach to formulate knowledge-based prescriptions is to conduct in silico screening for drugs and compounds that has the potential to disrupt viral protein functions. By evaluating the dataset from the \u201cShennong project\u201d, an in silico screening of the DrugBank library against SARS-CoV-2 proteins, we identified chlorogenic acid and rutin displayed a strong affinity with diverse viral proteins. Chlorogenic acid is naturally present in coffee in large quantity, and rutin is available as nutraceutical products, both compounds are considered safe to consume, hence could potentially aid the recovery or treatment for COVID-19 patients at low health risk. We emphasise that the results require further clinical clarification, the impact of this work shall be examined by professionals carefully.","type":"Research","database":"ChemRxiv","created":"2020-07-01"},{"id":364,"name":"Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2","author":"Vaishali Chandel, Prem Prakash Sharma, Sibi Raj, Ramesh Choudhari, Brijesh Rathi, Dhruv Kumar ","doi":"10.1080\/07391102.2020.1811773","abstract":"Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4\u2009Kcal\/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1\u2009Kcal\/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.","type":"Research","database":"PubMed","created":"2020-07-01"},{"id":363,"name":"Identification of Atovaquone, Ouabain and Mebendazole as FDA Approved Drugs Tar-geting SARS-CoV-2","author":"Ayman Farag, Ping Wang, Ian N. Boys, Jennifer L. Eitson, Maikke B. Ohlson, Wenchun Fan, Matthew B. McDougal, Mahmoud Ahmed, John W. Schoggins, Hesham Sadek","doi":"10.26434\/chemrxiv.12003930.v4","abstract":"The newly emerged coronavirus, SARS-CoV-2, and the resulting COVID-19 disease, has spread swiftly across the globe since its initial detection in December 2019. Given the heavy toll of this pandemic, therapeutic options for treatment are urgently needed. Here, we adopted a repositioning approach using in-silico molecular modeling to screen FDA-approved drugs with established safety profiles for potential inhibitory effects against SARS-CoV-2. We used structure-based drug design to screen more than 2000 FDA approved drugs against SARS-CoV-2 main protease enzyme (Mpro) substrate-binding pocket, focusing on two potential sites (central and terminal sites) to identify hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. We additionally screened the top hits from both sites for potential covalent binding via nucleophilic thiol attack of Cys 145. High-scoring candidates were then screened for antiviral activity against infectious SARS-CoV-2 in a cell-based viral replication assay, and counterscreened for toxicity. Atovaquone, Mebendazole, and Ouabain exhibited antiviral efficacy with IC50s well within their respective therapeutic plasma concentrations (low nanomolar to low micromolar range), and limited toxic effects. Notably, all three were predicted in docking studies to covalently bind SARS-CoV-2 Mpro, underscoring the utility of this in-silico approach for identifying putative antivirals for repurposing. These results do not confirm efficacy in animal models or in humans, but rather serve as a starting point for testing the antiviral potential of select FDA-approved drugs, either individually or in combination.","type":"Research","database":"ChemRxiv","created":"2020-06-23"},{"id":362,"name":"Plant-Derived Natural Polyphenols as Potential Antiviral Drugs Against SARS-CoV-2 via RNA\u2010dependent RNA Polymerase (RdRp) Inhibition: An In-Silico Analysis","author":"Satyam Singh, Avinash Sonawane, Sushabhan Sadhukhan","doi":"10.26434\/chemrxiv.12312263.v1","abstract":"The sudden outburst of Coronavirus disease (COVID-19) has left the entire world to a standstill. COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As per the report from the WHO, more than 4.5 million people have been infected by SARS-CoV-2 with more than 3,00,000 deaths across the globe. As of now, there is no therapeutic drug or vaccine approved for the treatment of SARS-CoV-2 infection. Hence, the outbreak of COVID-19 poses a massive threat to humans. Due to the time taking process of new drug design and development, drug repurposing might be the only viable solution to tackle COVID-19. RNA\u2010dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication, i.e. the synthesis of single-stranded RNA genomes, an absolutely necessary step for the survival and growth of the virus. Thus, RdRp is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols have been shown to inhibit enzymatic activities of RdRp of various RNA viruses including polio-virus type 1, parainfluenza virus type 3, and respiratory syncytial virus etc. More importantly, natural polyphenols have been used as a dietary supplementation for humans for a long time and played a beneficial role in immune homeostasis. Therefore, we were curious to study the binding of dietary polyphenols with RdRp of SARS-CoV-2 and assess their potential as an effective therapy for COVID-19. In this present work, we made a library of twenty potent polyphenols that have shown substantial therapeutic effects against various diseases. The polyphenols were successfully docked in the catalytic pocket of RdRp of SARS-CoV and SARS-CoV-2, and detailed studies on ADME prediction, toxicity prediction and target analysis were performed. The study reveals that EGCG, quercetagetin, and myricetin strongly bind to the active site of SARS-CoV-2 RdRp. Our studies suggest that EGCG, quercetagetin, and myricetin can inhibit RdRp and represent an effective therapy for COVID-19. ","type":"Research","database":"ChemRxiv","created":"2020-06-23"},{"id":361,"name":"Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets","author":"Su-Jin Park, Kwang-Min Yu, Young-Il Kim, Se-Mi Kim, Eun-Ha Kim, Seong-Gyu Kim, Eun Ji Kim, Mark Anthony B Casel, Rare Rollon, Seung-Gyu Jang, Min-Hyeok Lee, Jae-Hyung Chang, Min-Suk Song, Hye Won Jeong, Younho Choi, Weiqiang Chen, Woo-Jin Shin, Jae U Jung, Young Ki Choi","doi":"10.1128\/mBio.01114-20","abstract":"Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved\/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial. ","type":"Research","database":"PubMed","created":"2020-06-23"},{"id":360,"name":"Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease","author":"Abhik Kumar Ray, Parth Sarthi Sen Gupta, Saroj Kumar Panda, Satyaranjan Biswal, Malay Kumar Rana","doi":"10.26434\/chemrxiv.12278066.v1","abstract":"COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal\/mol), out of which the top two drugs Velpatasvir (-9.1 kcal\/mol) and Glecaprevir (-9.0 kcal\/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor \u03b1-ketoamide 13B (-6.7 kcal\/mol) or Indinavir (-7.5 kcal\/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The in-silico efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway.","type":"Research","database":"ChemRxiv","created":"2020-06-23"},{"id":359,"name":"Potential Drugs Targeting Nsp16 Protein May Corroborates a Promising Approach to Combat SARSCoV-2 Virus","author":"Uma Shankar, Neha Jain, Prativa Majee, Subodh Kumar Mishra, Brijesh Rathi, Amit Kumar","doi":"10.26434\/chemrxiv.12279671.v1","abstract":"The recent ongoing pandemic caused by SARS-CoV-2 continues to impose devastating impacts and is accountable for the loss of more than 250,000 human lives within a short span of four months. This urges immediate therapeutic measures to control the impact of this disease. One of the most conserved and potentially druggable sites is the Nsp16 active site that performs the 2\u2019-O-methyltransferase activity and puts a 5\u2019 cap on the viral RNA molecules. This allows them to mimic endogenous transcripts for the efficient translation of viral proteins and evasion of the immune response. Herein, we screened three libraries of compounds (>5500) with chemical diversity to identify hits against Nsp16 active site of SARS-CoV-2. From each library a top hit was identified, namely Velpatasvir from the FDA compounds; JFD00244 from the LOPAC library and compound 6 from the SAM based analog library. Interestingly, all three hits showed higher affinity than the positive controls. Velpatasvir is a known anti-viral drug used against Hepatitis C virus, and JFD00244 is a SIRT2 inhibitor. 100ns molecular simulation studies showed all three molecules to have stable and energetically favourable interactions with the active site of Nsp16. In summary, this investigation identified three potential drug candidates that are predicted to be potent Nsp16 inhibitors and could be pursued further in cell-based studies. ","type":"Research","database":"ChemRxiv","created":"2020-06-23"},{"id":358,"name":"Ritonavir May Inhibit Exoribonuclease Activity of Nsp14 from the SARS-CoV-2 Virus and Potentiate the Activity of Chain Terminating Drugs","author":"Naveen Narayanan, Deepak T Nair","doi":"10.1016\/j.ijbiomac.2020.12.038","abstract":"SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3\u2032 to 5\u2032 exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3\u2032 nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.","type":"Research","database":"PMC","created":"2020-06-23"},{"id":357,"name":"Accelerating drug development through repurposed FDA approved drugs for COVID-19: speed is important, not haste","author":"James T. Gordy, Kaushiki Mazumdar, Noton K. Dutta","doi":"10.1128\/AAC.00857-20","abstract":"A life-threatening, emerging respiratory disease called Coronavirus Disease 2019 (COVID-19) 26 originated in the city of Wuhan in China's Hubei province in December, 2019 and has been classified as 27 an international pandemic by the World Health Organization...","type":"Other","database":"PubMed","created":"2020-06-15"},{"id":356,"name":"The Use of Chloroquine and Hydroxychloroquine in COVID-19 and Cardiovascular Implications: Understanding Safety Discrepancies to Improve Interpretation and Design of Clinical Trials","author":"Ohad Oren, Eric H. Yang, Ty J. Gluckman, Erin D. Michos, Roger S. Blumenthal, Bernard J. Gersh","doi":"10.1161\/CIRCEP.120.008688","abstract":null,"type":"Research","database":"PubMed","created":"2020-06-15"},{"id":355,"name":"COVID-19: An Update about the Discovery Clinical Trial","author":"Jean Jacques Vanden Eynde","doi":"10.3390\/ph13050098","abstract":"Finding efficacious and safe treatments for COVID-19 emerges as a crucial need in order to control the spread of the pandemic. Whereas plasma therapy attracts much interest, the European project Discovery focuses on the potentialities of small molecules like remdesivir, the combination of lopinavir\/ritonavir, hydroxychloroquine, and chloroquine. Results recently published on the clinical evaluation of those drugs are compiled in this brief report, although complete data are still impatiently awaited.","type":"Comment","database":"PubMed","created":"2020-06-12"},{"id":354,"name":"A comprehensive review on drug repositioning against coronavirus disease 2019 (COVID19)","author":"Maryam Rameshrad, Majid Ghafoori, Amir Hooshang Mohammadpour, Mohammad Javad Dehghan Nayeri & Hossein Hosseinzadeh","doi":"10.1007\/s00210-020-01901-6","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the reason for this ongoing pandemic infection diseases termed coronavirus disease 2019 (COVID-19) that has emerged since early December 2019 in Wuhan City, Hubei Province, China. In this century, it is the worst threat to international health and the economy. After 4 months of COVID-19 outbreak, there is no certain and approved medicine against it. In this public health emergency, it makes sense to investigate the possible effects of old drugs and find drug repositioning that is efficient, economical, and riskless process. Old drugs that may be effective are from different pharmacological categories, antimalarials, anthelmintics, anti-protozoal, anti-HIVs, anti-influenza, anti-hepacivirus, antineoplastics, neutralizing antibodies, immunoglobulins, and interferons. In vitro, in vivo, or preliminary trials of these drugs in the treatment of COVID-19 have been encouraging, leading to new research projects and trials to find the best drug\/s. In this review, we discuss the possible mechanisms of these drugs against COVID-19. Also, it should be mentioned that in this manuscript, we discuss preliminary rationales; however, clinical trial evidence is needed to prove them. COVID-19 therapy must be based on expert clinical experience and published literature and guidelines from major health organizations. Moreover, herein, we describe current evidence that may be changed in the future.","type":"Review","database":"PubMed","created":"2020-06-12"},{"id":353,"name":"Response to: Optimizing Hydroxychloroquine Dosing for Patients With COVID\u201019: An Integrative Modeling Approach for Effective Drug Repurposing","author":"Joseph F. Standing","doi":"10.1002\/cpt.1872","abstract":null,"type":"Comment","database":"PubMed","created":"2020-06-12"},{"id":352,"name":"Repurposing of drugs for Covid-19: a systematic review and meta-analysis","author":"P. Kotecha, A. Light, E. Checcucci, D. Amparore, C. Fiori, F. Porpiglia, P. Dasgupta, O. Elhage","doi":"10.1101\/2020.06.07.20124677","abstract":"Objective: The aim of this systematic review is to evaluate the data currently available regarding the repurposing of different drugs for Covid-19 treatment. Participants with suspected or diagnosed Covid-19 will be included. The interventions being considered are drugs being repurposed, and comparators will include standard of care treatment or placebo. Methods: We searched Ovid-MEDLINE, EMBASE, Cochrane library, clinical trial registration site in the UK(NIHR), Europe (clinicaltrialsregister.eu), US (ClinicalTrials.gov) and internationally (isrctn.com), and reviewed the reference lists of articles for eligible articles published up to April 22, 2020. All studies in English that evaluated the efficacy of the listed drugs were included. Cochrane RoB 2.0 and ROBINS-I tool were used to assess study quality. This systematic review adheres to the PRISMA guidelines. The protocol is available at PROSPERO (CRD42020180915). Results: From 708 identified studies or clinical trials, 16 studies and 16 case reports met our eligibility criteria. Of these, 6 were randomized controlled trials (763 patients), 7 cohort studies (321 patients) and 3 case series (191 patients). Chloroquine (CQ) had a 100% discharge rate compared to 50% with lopinavir-ritonavir at day 14, however a trial has recommended against a high dosage due to cardiotoxic events. Hydroxychloroquine (HCQ) has shown no significant improvement in negative seroconversion rate which is also seen in our meta-analysis (p=0.68). Adverse events with HCQ have a significant difference compared to the control group (p=0.001). Lopinavir-ritonavir has shown no improvement in time to clinical improvement which is seen in our meta-analyses (p=0.1). Remdesivir has shown no significant improvement in time to clinical improvement but this trial had insufficient power. Discussion: Due to the paucity in evidence, it is difficult to establish the efficacy of these drugs in the treatment of Covid-19 as currently there is no significant clinical effectiveness of the repurposed drugs. Further large clinical trials are required to achieve more reliable findings. A risk-benefit analysis is required on an individual basis to weigh out the potential improvement in clinical outcome and viral load reduction compared to the risks of the adverse events.","type":"Review","database":"MedRxiv","created":"2020-06-11"},{"id":351,"name":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","author":"Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Kr\u00fcger, Tanja Herrler, Sandra Erichsen, Tobias S Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A M\u00fcller, Christian Drosten , Stefan P\u00f6hlmann","doi":"10.1016\/j.cell.2020.02.052 ","abstract":"The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention. ","type":"Research","database":"PubMed","created":"2020-06-10"},{"id":350,"name":"Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells: Nafamostat is the most potent antiviral drug candidate","author":"Meehyun Ko, Sangeun Jeon, Wang-Shick Ryu, Seungtaek Kim","doi":"10.1101\/2020.05.12.090035","abstract":"Drug repositioning represents an effective way to control the current COVID-19 pandemic. Previously, we identified 24 FDA-approved drugs which exhibited substantial antiviral effect against SARS-CoV-2 in Vero cells. Since antiviral efficacy could be altered in different cell lines, we developed an antiviral screening assay with human lung cells, which is more appropriate than Vero cell. Comparative analysis of antiviral activities revealed that nafamostat is the most potent drug in human lung cells (IC50 = 0.0022\u00b5M).","type":"Research","database":"BioRxiv","created":"2020-06-09"},{"id":349,"name":"Recent advances of therapeutic targets and potential drugs of COVID-19.","author":"Zhang W, Zhang P, Wang G, Cheng W, Chen J, Zhang X","doi":"10.1691\/ph.2020.0431","abstract":"Since December 2019, numerous cases of coronavirus disease 2019 (COVID-19) caused by the infection of the novel coronavirus (2019-nCoV) have been confirmed in Wuhan, China. The outbreak of 2019-nCoV in China embodied a significant and urgent threat to global health. 2019-nCoV was a new, highly contagious coronavirus discovered following the outbreak of SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV). The novel coronavirus can cause severe respiratory disease and even death. However, no specific therapeutic drugs have been developed clinically thus far. This article examines the potential of therapeutic drugs by assessing the structure of 2019-nCoV, its mechanism in invading host cells, and the anti-viral mechanism of the human autoimmune system. We also review the latest research regarding the progress of potential therapeutic drugs and provide references for new drug developments of COVID-19.","type":"Review","database":"PubMed","created":"2020-06-09"},{"id":348,"name":"Computational Discovery of Small Drug-like Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease","author":"Alexander M. Andrianov, Yuri V. Kornoushenko, Anna D. Karpenko, Ivan P. Bosko, Alexander Tuzikov","doi":"10.26434\/chemrxiv.12275390.v1","abstract":"A computational approach to in silico drug discovery was carried out to identify small druglike compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (MPro). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-MPro structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 MPro were generated by molecular docking and optimized by the quantum chemical method PM7. At the final point, analysis of the interaction modes of the identified compounds with MPro and prediction of their binding affinity were carried out. Calculation revealed 5 top-ranking compounds that exhibited a high affinity to the active site of SARS-CoV-2 MPro. Insights into the ligand\uf02dMPro models indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 MPro, in line with the low values of binding free energy and dissociation constant. Mechanism of binding of these compounds to MPro is generally provided by hydrogen bonds and van der Waals interactions with the functionally important residues of the enzyme active site, such as His-41, Leu-141, His-163, Met-165, and Glu166. In addition, individual ligands form salt bridges with the MPro residues His-163 or Glu-166 and participate in specific \uf070-\uf070 interactions with the catalytic dyad residue His-41. The data obtained show that the identified X77-mimetic candidates may serve as good scaffolds for the design of novel antiviral agents able to target the active site of SARS-CoV-2 MPro.","type":"Research","database":"ChemRxiv","created":"2020-06-09"},{"id":347,"name":"Ro5 Bioactivity Lab: Identification of Drug Candidates for COVID-19","author":"Zeyu Yang, Orestis Bastas, Mikhail Demtchenko, Aurimas Pabrinkis, Cooper Stergis, Jamieson Danius, Ba\u010dkis Charles, Dazler Knuff, \u017dygimantas Jo\u010dys, Roy Tal","doi":"10.26434\/chemrxiv.12275741.v1","abstract":"The public health emergency known as the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a large number of deaths worldwide and major socioeconomic disruption. To date, no broadly effective antiviral treatment or vaccine has been developed for COVID-19. In response to this dire situation, Ro5 deployed its AI Lab to accelerate the search for potential treatments. This report focuses on our use of the Ro5 Bioactivity model, which has been designed to predict the inhibitory activity of small molecules against protein targets. The model screened a vast range of compounds in silico to uncover potential inhibitors of the SARS-CoV-2 3CL protease. We hereby present the most propitious candidates from this screen. The highest-ranking molecules include Nelfinavir, Saquinavir, Itacitinib, Kynostatin-272, BOG-INS-6c2-1, and BEN-VAN-d2b-11. Subsequent docking simulations corroborate their plausibility as 3CLpro inhibitors. Nelfinavir and Itacitinib hold the most promise for drug repurposing, among all the molecules proposed herein, due to their high predicted inhibition and affinity against the 3CL protease, favourable pharmacokinetics, and encouraging experimental data for treating viral replication and hyperinflammation, respectively.","type":"Research","database":"ChemRxiv","created":"2020-06-09"},{"id":346,"name":"Use of antimalarial drugs in the treatment of COVID-19: A window of opportunity?","author":"Lasheras I, Santab\u00e1rbara J","doi":"10.1016\/j.medcli.2020.04.004","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-06-09"},{"id":345,"name":"Do novel drugs for diabetes will help in COVID-19? Another brick in the wall?","author":"Krejner-Bienias A, Grzela K, Grzela T","doi":"10.1111\/1753-0407.13050","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-06-09"},{"id":344,"name":"Designing of improved drugs for COVID-19: Crystal structure of SARS-CoV-2 main protease Mpro","author":"Mengist HM, Fan X, Jin T","doi":"10.1038\/s41392-020-0178-y","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-06-09"},{"id":343,"name":"Use of Triiodothyronine to Treat Critically Ill COVID-19 Patients: A New Clinical Trial","author":"Pantos C, Tseti I, Mourouzis I","doi":"10.1186\/s13054-020-02934-2","abstract":"no abstract available","type":"Comment","database":"PubMed","created":"2020-06-09"},{"id":342,"name":"Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel in Silico Method","author":"Milan Sencanski, Vladimir Perovic, Snezana Pajovic, Miroslav Adzic, Slobodan Paessler, Sanja Glisic","doi":"10.3390\/molecules25173830","abstract":"The SARS-CoV-2 outbreak caused an unprecedented global public health threat,\r\nhaving a high transmission rate with currently no drugs or vaccines approved. An alternative\r\npowerful additional approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2\r\nmain protease is essential for viral replication and an attractive drug target. In this study, we used\r\nthe virtual screening protocol with both long-range and short-range interactions to select candidate\r\nSARS-CoV-2 main protease inhibitors. First, the Informational spectrum method applied for small\r\nmolecules was used for searching the Drugbank database and further followed by molecular docking.\r\nAfter in silico screening of drug space, we identified 57 drugs as potential SARS-CoV-2 main protease\r\ninhibitors that we propose for further experimental testing.\r\n","type":"Research","database":"PubMed","created":"2020-06-09"},{"id":341,"name":"Old and re-purposed drugs for the treatment of COVID-19","author":"Shio-Shin Jean, Po-Ren Hsueh","doi":"10.1080\/14787210.2020.1771181","abstract":"Introduction\r\n\r\nThe coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed since December 2019. It has caused a global pandemic with more than three hundred thousand case fatalities. However, apart from supportive care by respirators, no standard medical therapy is validated.\r\n\r\nAreas covered\r\n\r\nThis paper presents old drugs with potential in vitro efficacy against SARS-CoV-2. The in vitro database, adverse effects, and potential toxicities of these drugs are reviewed regarding their feasibility of clinical prescription for the treatment of patients with COVID-19. To obtain convincing recommendations, we referred to opinions from the US National Institute of Health regarding drugs repurposed for COVID-19 therapy.\r\n\r\nExpert opinion\r\n\r\nAlthough strong evidence of well-designed randomized controlled studies regarding COVID-19 therapy is presently lacking, remdesivir, teicoplanin, hydroxychloroquine (not in combination with azithromycin), and ivermectin might be effective antiviral drugs and are deemed promising candidates for controlling SARS-CoV-2. In addition, tocilizumab might be considered as the supplementary treatment for COVID-19 patients with cytokine release syndrome. In future, clinical trials regarding a combination of potentially effective drugs against SARS-CoV-2 need to be conducted to establish the optimal regimen for the treatment of patients with moderate-to-severe COVID-19.\r\n","type":"Review","database":"PubMed","created":"2020-06-08"},{"id":340,"name":"Treatments for COVID-19: emerging drugs against the coronavirus","author":"Francesco Pot\u00ec, Cristina Pozzoli , Maristella Adami, Enzo Poli, Lucio G. Costa","doi":"10.23750\/abm.v91i2.9639","abstract":"The Coronavirus disease 19 (COVID-19) outbreak has been recognized as a global threat to public health. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and no effective therapies currently exist against this novel viral agent. Along with extensive public health measures, an unprecedented global effort in identifying effective drugs for the treatment is being implemented. Potential drug targets are emerging as the result of a fast-evolving understanding of SARS-CoV-2 virology, host response to the infection, and clinical course of the disease. This brief review focuses on the latest and most promising pharmacological treatments against COVID-19 currently under investigation and discuss their potential use based on either documented efficacy in similar viral infections, or their activity against inflammatory syndromes. Ongoing clinical trials are also emphasized.","type":"Review","database":"PubMed","created":"2020-06-07"},{"id":339,"name":"Several FDA-approved drugs effectively inhibit SARS-CoV-2 infection in vitro","author":"Hua-Long Xiong, Jia-Li Cao, Chen-Guang Shen, Jian Ma, Xiao_Yang Qiao, Tian_Shu Shi, Yang Yang, Sheng-Xiang Ge, Jun Zhang, Tian-Ying Zhang, Quan Yuan, Ning-Shao Xia","doi":"10.3389\/fphar.2020.609592","abstract":"To identify drugs that are potentially used for the treatment of COVID-19, the potency of 1403 FDA-approved drugs were evaluated using a robust pseudovirus assay and the candidates were further confirmed by authentic SARS-CoV-2 assay. Four compounds, Clomiphene (citrate), Vortioxetine, Vortioxetine (hydrobromide) and Asenapine (hydrochloride), showed potent inhibitory effects in both pseudovirus and authentic virus assay. The combination of Clomiphene (citrate), Vortioxetine and Asenapine (hydrochloride) is much more potent than used alone, with IC50 of 0.34 \u03bcM.","type":"Research","database":"PMC","created":"2020-06-06"},{"id":337,"name":"Knowledge\u2010based structural models of SARS\u2010CoV\u20102 proteins and their complexes with potential drugs","author":"Atsushi Hijikata, Clara Shionyu\u2010Mitsuyama, Setsu Nakae, Masafumi Shionyu, Motonori Ota, Shigehiko Kanaya, Tsuyoshi Shirai","doi":"10.1002\/1873-3468.13806","abstract":"The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID\u201019) caused by the novel coronavirus SARS\u2010CoV\u20102 a pandemic. There is, however, no confirmed anti\u2010COVID\u201019 therapeutic currently. In order to assist structure\u2010based discovery efforts for repurposing drugs against this disease, we constructed knowledge\u2010based models of SARS\u2010CoV\u20102 proteins and compared the ligand molecules in the template structures with approved\/experimental drugs and components of natural medicines. Our theoretical models suggest several drugs, such as carfilzomib, sinefungin, tecadenoson, and trabodenoson, that could be further investigated for their potential for treating COVID\u201019.","type":"Research","database":"PubMed","created":"2020-06-06"},{"id":336,"name":"In Silico Trial to test COVID-19 candidate vaccines: a case study with UISS platform","author":"Giulia Russo, Marzio Pennisi, Marco Viceconti, Francesco Pappalardo","doi":"10.1101\/2020.05.06.080630","abstract":"SARS-CoV-2 is a severe respiratory infection that infects humans. Its outburst entitled it as a pandemic emergence. To get a grip on this outbreak, specific preventive and therapeutic interventions are urgently needed. It must be said that, until now, there are no existing vaccines for coronaviruses. To promptly and rapidly respond to pandemic events, the application of in silico trials can be used for designing and testing medicines against SARS-CoV-2 and speed-up the vaccine discovery pipeline, predicting any therapeutic failure and minimizing undesired effects. Here, we present an in silico platform that showed to be in very good agreement with the latest literature in predicting SARS-CoV-2 dynamics and related immune system host response. Moreover, it has been used to predict the outcome of one of the latest suggested approach to design an effective vaccine, based on monoclonal antibody. Universal Immune System Simulator (UISS) in silico platform is potentially ready to be used as an in silico trial platform to predict the outcome of vaccination strategy against SARS-CoV-2.","type":"Research","database":"BioRxiv","created":"2020-06-06"},{"id":335,"name":"A human monoclonal antibody blocking SARS-CoV-2 infection","author":"Chunyan Wang, Wentao Li, Dubravka Drabek, Nisreen M. A. Okba, Rien van Haperen, Albert D. M. E. Osterhaus, Frank J. M. van Kuppeveld, Bart L. Haagmans, Frank Grosveld & Berend-Jan Bosch","doi":"10.1038\/s41467-020-16256-y","abstract":"The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.","type":"Research","database":"PubMed","created":"2020-06-06"},{"id":334,"name":"Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine","author":"Marion Plaze, David Attali, Matthieu Prot, Anne-C\u00e9cile Petit, Michael Blatzer, Fabien Vinckier, Laurine Levillayer, Jeanne Chiaravalli, Florent Perin-Dureau, Arnaud Cachia, G\u00e9rard Friedlander, Fabrice Chr\u00e9tien, Etienne Simon-Loriered, Rapha\u00ebl Gaillard","doi":"10.1016\/j.ijantimicag.2020.106274","abstract":"Introduction\r\nUrgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells.\r\n\r\nMaterials and methods\r\nMonkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells.\r\n\r\nResults\r\nCPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC50) of 8.2 \u00b5M, half maximal cytotoxic concentration (CC50) of 13.5 \u00b5M, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC50 of 11.3 \u00b5M, CC50 of 23.1 \u00b5M and SI of 2.04.\r\n\r\nDiscussion\r\nAlthough the measured SI values are low, the IC50 values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19.\r\n\r\nConclusions\r\nThese preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.","type":"Research","database":"BioRxiv","created":"2020-05-30"},{"id":333,"name":"Antiretroviral Drug Activity and Potential for Pre-Exposure Prophylaxis Against COVID-19 and HIV Infection","author":"Dennis C. Copertino Jr., Bruno Lima, Rodrigo Duarte, Timothy Wilkin, Roy Gulick, Miguel de Mulder Rougvie, Douglas Nixon","doi":"10.26434\/chemrxiv.12250199.v1","abstract":"COVID-19 is the disease caused by SARS-CoV-2, and has led to over 250,000 deaths by May 2020. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify those drugs that can specifically target the overactive immune response are ongoing around the world. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a recent clinical trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19 disease. However, anecdotal reports suggest either reduced infection or a course of milder COVID-19 disease in people living with HIV (PLWH) on ARVs. We hypothesized ARVs other than lopinavir and ritonavir might be responsible for such effects. Here, we used chemoinformatic analyses to predict which ARVs would bind and potentially inhibit the SARS-CoV-2 main protease or RNA-dependent RNA polymerase enzymes, and identified a number of ARVs which bind to SARS-CoV-2 enzymes in silico. Our study identified HIV nucleoside\/nucleotide analogue reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, tenofovir, zidovudine), HIV protease inhibitors (ASC09, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) and an HIV pharmacokinetic booster (cobicistat), as drug candidates with effective in silico binding to one or both viral enzymes. Tenofovir and emtricitabine are FDA-approved as HIV pre-exposure prophylaxis (PrEP) and have an extensive safety profile of use in populations without HIV. Existing or new combinations of antiretroviral drugs could potentially prevent or ameliorate the course of COVID-19, if shown to inhibit SARS-CoV-2 in vitro and\/or in clinical trials. Further studies are needed to establish the activity of ARVs for treatment or prevention of SARS-CoV-2 infection.","type":"Research","database":"ChemRxiv","created":"2020-05-28"},{"id":332,"name":"Repurposing low-molecular-weight drugs against the main protease of SARS-CoV-2","author":"J. Gao, L. Zhang, X. Liu, F. Li, R. Ma, Z. Zhu, J. Zhang, J. Wu, Y. Shi, Y. Pan, Y. Ge, K. Ruan ","doi":"10.1101\/2020.05.05.079848","abstract":"The pandemic of COVID-19, which is caused by the SARS-CoV-2 virus infection, has posed a threat to global healthcare system. The repurposing drug is one of the feasible ways for the emergency treatment. As the low-molecular-weight drugs have a higher possibility to fully match the interactions with essential targets of SARS-CoV-2, we propose a strategy to uncover such drugs using the fragment-based approach.Here, using the ligand-observed and protein-observed fragment screening approach, we identified niacin and hit 1 binding to the catalytic pocket of the main protease of SARS-CoV-2 (Mpro), thus modestlyinhibited the enzymatic activity of Mpro.The chemical shift perturbations induced by niacin and hit 1 indicates a partial overlap of their binding sites, i.e., the catalytic pocket of Mpro may accommodate derivatives with larger molecular size. We hence searched drugs containing the niacin or hit 1 pharmocophore,and uncovered carmofur, bendamustine, triclabendazole and emedastine, which demonstrated higher potency of inhibiting protease activity than the fragment screening hits. Our work demonstrated that fragment-based approach is a feasible way to uncover low-molecular-weight drugs against SARS-CoV-2, and potentially other targets without specific drug yet.","type":"Research","database":"BioRxiv","created":"2020-05-27"},{"id":331,"name":"Crystal Structure of SARS-CoV-2 Nucleocapsid Protein RNA Binding Domain Reveals Potential Unique Drug Targeting Sites","author":"Sisi Kang, Mei Yang, Zhongsi Hong, Liping Zhang, Zhaoxia Huang, Xiaoxue Chen, Suhua He, Ziliang Zhou, Zhechong Zhou, Qiuyue Chen, Yan Yan, Changsheng Zhang, Hong Shan, Shoudeng Chen","doi":"10.1016\/j.apsb.2020.04.009","abstract":"The outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus continually led to worldwide human infections and deaths. Currently, there is no specific viral protein-targeted therapeutics. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein remains unclear. Herein, we have determined the 2.7 \u00c5 crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although the overall structure is similar as other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the \u03b2-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2. ","type":"Research","database":"PubMed","created":"2020-05-26"},{"id":330,"name":"Genomics Functional Analysis and Drug Screening of SARS-CoV-2","author":"Chen L, Zhong L","doi":"10.1016\/j.gendis.2020.04.002","abstract":"A novel coronavirus appeared in Wuhan, China has led to major outbreaks. Recently, rapid classification of virus species, analysis of genome and screening for effective drugs are the most important tasks. In the present study, through literature review, sequence alignment, ORF identification, motif recognition, secondary and tertiary structure prediction, the whole genome of SARS-CoV-2 were comprehensively analyzed. To find effective drugs, the parameters of binding sites were calculated by SeeSAR. In addition, potential miRNAs were predicted according to RNA base-pairing. After prediction by using NCBI, WebMGA and GeneMark and comparison, a total of 8 credible ORFs were detected. Even the whole genome have great difference with other CoVs, each ORF has high homology with SARS-CoVs (>90%). Furthermore, domain composition in each ORFs was also similar to SARS. In the DrugBank database, only 7 potential drugs were screened based on the sequence search module. Further predicted binding sites between drug and ORFs revealed that 2-(N-Morpholino)-ethanesulfonic acid could bind 1# ORF in 4 different regions ideally. Meanwhile, both benzyl (2-oxopropyl) carbamate and 4-(dimehylamina) benzoic acid have bene demonstrated to inhibit SARS-CoV infection effectively. Interestingly, 2 miRNAs (miR-1307-3p and miR-3613-5p) were predicted to prevent virus replication via targeting 3'-UTR of the genome or as biomarkers. In conclusion, the novel coronavirus may have consanguinity with SARS. Drugs used to treat SARS may also be effective against the novel virus. In addition, altering miRNA expression may become a potential therapeutic schedule. ","type":"Research","database":"PubMed","created":"2020-05-26"},{"id":329,"name":"Identification of new anti-nCoV drug chemical compounds from Indian spices exploiting SARS-CoV-2 main protease as target","author":"Umesh, Kundu D, Selvaraj C, Singh SK, Dubey VK","doi":"10.1080\/07391102.2020.1763202","abstract":"The 2019-novel coronavirus (nCoV) has caused a global health crisis by causing coronavirus disease-19 (COVID-19) pandemic in the human population. The unavailability of specific vaccines and anti-viral drug for nCoV, science demands sincere efforts in the field of drug design and discovery for COVID-19. The novel coronavirus main protease (SARS-CoV-2 Mpro) play a crucial role during the disease propagation, and hence SARS-CoV-2 Mpro represents as a drug target for the drug discovery. Herein, we have applied bioinformatics approach for screening of chemical compounds from Indian spices as potent inhibitors of SARS-CoV-2 main protease (PDBID: 6Y84). The structure files of Indian spices chemical compounds were taken from PubChem database or Zinc database and screened by molecular docking, by using AutoDock-4.2, MGLTools-1.5.6, Raccoon virtual screening tools. Top 04 hits based on their highest binding affinity were analyzed. Carnosol exhibited highest binding affinity -8.2 Kcal\/mol and strong and stable interactions with the amino acid residues present on the active site of SARS-CoV-2 Mpro. Arjunglucoside-I (-7.88 Kcal\/mol) and Rosmanol (-7.99 Kcal\/mol) also showed a strong and stable binding affinity with favourable ADME properties. These compounds on MD simulations for 50ns shows strong hydrogen-bonding interactions with the protein active site and remains stable inside the active site. Our virtual screening results suggest that these small chemical molecules can be used as potential inhibitors against SARS-CoV-2 Mpro and may have an anti-viral effect on nCoV. However, further validation and investigation of these inhibitors against SARS-CoV-2 main protease are needed to claim their candidacy for clinical trials.","type":"Research","database":"PubMed","created":"2020-05-26"},{"id":328,"name":"Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids","author":"Xiaohua Duan, Yuling Han, Liuliu Yang, Benjamin E. Nilsson-Payant, Pengfei Wang, Tuo Zhang, Jenny Xiang, Dong Xu, Xing Wang, Skyler Uhl, Yaoxing Huang, Huanhuan Joyce Chen, Hui Wang, Benjamin tenOever, Robert E. Schwartz, David. D. Ho, Todd Evans, Fong Cheng Pan, Shuibing Chen","doi":"10.1101\/2020.05.02.073320","abstract":"The current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.","type":"Research","database":"BioRxiv","created":"2020-05-26"},{"id":327,"name":"Potential anti-SARS-CoV-2 drug candidates identified through virtual screening of the ChEMBL database for compounds that target the main coronavirus protease.","author":"M. Tsuji","doi":"10.1002\/2211-5463.12875","abstract":"A novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS\u2010CoV\u20102], or 2019 novel coronavirus [2019\u2010nCoV]) has been identified as the pathogen of coronavirus disease 2019 (COVID\u201019). The main protease (Mpro, also called 3\u2010chymotrypsin\u2010like protease [3CLpro]) of SARS\u2010CoV\u20102 is a potential target for treatment of COVID\u201019. A Mpro homodimer structure suitable for docking simulations was prepared using a crystal structure (PDB ID: 6Y2G; resolution 2.20 \u00c5). Structural refinement was performed in the presence of peptidomimetic \u03b1\u2010ketoamide inhibitors, which were previously disconnected from each Cys145 of the Mpro homodimer, and energy calculations were performed. Structure\u2010based virtual screenings were performed using the ChEMBL database. Through a total of 1,485,144 screenings, 64 potential drugs (11 approved, 14 clinical, and 39 preclinical drugs) were predicted to show high binding affinity with Mpro. Additional docking simulations for predicted compounds with high binding affinity with Mpro suggested that 28 bioactive compounds may have potential as effective anti\u2010SARS\u2010CoV\u20102 drug candidates. The procedure used in this study is a possible strategy for discovering anti\u2010SARS\u2010CoV\u20102 drugs from drug libraries that may significantly shorten the clinical development period with regard to drug repositioning.","type":"Research","database":"PubMed","created":"2020-05-25"},{"id":326,"name":"Convalescent Plasma to Treat Coronavirus Disease 2019 (COVID-19): Considerations for Clinical Trial Design","author":"P. Barone,  R. A. DeSimone","doi":"10.1111\/trf.15843","abstract":"At present, prevention and supportive care dominate the approach to coronavirus disease 2019 (COVID\u201019). Treatments directly targeting the virus and the inflammatory response to it remain investigational. Convalescent plasma (CP) is one such therapy. Here we will review the results of studies on CP use for treating other viral diseases, namely severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, Ebola virus (EBOV), and respiratory syncytial virus (RSV), followed by recent case series on its use for treating COVID\u201019. We will then summarize Food and Drug Administration (FDA) requirements for administering CP for COVID\u201019 and review trials being conducted in North America.","type":"Review","database":"PubMed","created":"2020-05-23"},{"id":325,"name":"Delivering Benefits at Speed through Real-World Repurposing of Off-Patent Drugs: The COVID-19 Pandemic as a Case in Point.","author":"M. Rogosnitzky, E. Berkowitz, A. R. Jadad","doi":"10.2196\/19199","abstract":"Real-world drug repurposing-the immediate \"off-label\" prescribing of drugs to address urgent clinical needs-is a widely overlooked opportunity. Off-label prescribing (ie, for a nonapproved indication) is legal in most countries and tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, health crises may mean that real-world repurposing is the only realistic source for solutions. Optimal real-world repurposing requires a track record of safety, affordability, and access for drug candidates. Although thousands of such drugs are already available, there is no central repository of off-label uses to facilitate immediate identification and selection of potentially useful interventions during public health crises. Using the current coronavirus disease (COVID-19) pandemic as an example, we provide a glimpse of the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and targeted toward the underlying pathophysiology that makes COVID-19 so deadly. This paper briefly summarizes why cimetidine or famotidine, dipyridamole, fenofibrate or bezafibrate, and sildenafil citrate are worth considering for patients with COVID-19. Clinical trials to assess efficacy are already underway for famotidine, dipyridamole, and sildenafil, and further trials of all these agents will be important in due course. These examples also reveal the unlimited opportunity to future-proof our health care systems by proactively mining, synthesizing, cataloging, and evaluating the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.","type":"Review","database":"PubMed","created":"2020-05-23"},{"id":324,"name":"The anti\u2010HIV drug nelfinavir mesylate (Viracept) is a potentinhibitor of cell fusion caused by the SARSCoV\u20102 spike (S)glycoprotein warranting further evaluation as an antiviralagainst COVID\u201019 infections","author":"F. Musarrat, V. Chouljenko, A. Dahal, R. Nabi, T. Chouljenko, S. D. Jois, K. G. Kousoulas","doi":"10.1002\/jmv.25985","abstract":"Severe acute respiratory syndrome coronavirus\u20102 (SARS CoV\u20102) is the causative agent of the coronavirus disease\u20102019 (COVID\u201019) pandemic. Coronaviruses enter cells via fusion of the viral envelope with the plasma membrane and\/or via fusion of the viral envelope with endosomal membranes after virion endocytosis. The spike (S) glycoprotein is a major determinant of virus infectivity. Herein, we show that the transient expression of the SARS CoV\u20102 S glycoprotein in Vero cells caused extensive cell fusion (formation of syncytia) in comparison to limited cell fusion caused by the SARS S glycoprotein. Both S glycoproteins were detected intracellularly and on transfected Vero cell surfaces. These results are in agreement with published pathology observations of extensive syncytia formation in lung tissues of patients with COVID\u201019. These results suggest that SARS CoV\u20102 is able to spread from cell\u2010to\u2010cell much more efficiently than SARS effectively avoiding extracellular neutralizing antibodies. A systematic screening of several drugs including cardiac glycosides and kinase inhibitors and inhibitors of human immunodeficiency virus (HIV) entry revealed that only the FDA\u2010approved HIV protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S\u2010n\u2010 and S\u2010o\u2010mediated cell fusion with complete inhibition at a 10\u2010\u03bcM concentration. In\u2010silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S\u2010n\u2010 and S\u2010o\u2010mediated membrane fusion. Also, it is possible that nelfinavir may act to inhibit S proteolytic processing within cells. These results warrant further investigations of the potential of nelfinavir mesylate to inhibit virus spread at early times after SARS CoV\u20102 symptoms appear.","type":"Research","database":"PubMed","created":"2020-05-23"},{"id":323,"name":"Potential Therapeutic Targets and Promising Drugs for Combating SARS\u2010CoV\u20102","author":"Hong Zhou, Yan Fang, Tao Xu, Wei-Jian Ni, Ai-Zong Shen, Xiao-Ming Meng","doi":"10.1111\/bph.15092","abstract":"As of April 9, 2020, a novel coronavirus (SARS-CoV-2) had caused 89,931 deaths and 1,503,900 confirmed cases worldwide, which indicates an increasingly severe and uncontrollable situation. Initially, little was known about the virus. As research continues, we have learned the genome structure, epidemiological and clinical characteristics and pathogenic mechanisms of SARS-CoV-2. Based on these discoveries, identifying potential targets involved in the processes of virus pathogenesis is urgently needed, and discovering or developing promising drugs based on potential targets is the most pressing need. Therefore, we summarize the potential therapeutic targets involved in virus pathogenesis and discuss the advancements, possibilities and significance of promising drugs based on these targets for treating SARS-CoV-2. This review will facilitate the identification of potential targets and provide promising clues for drug development that can be translated into clinical applications for combating SARS-CoV-2.","type":"Review","database":"PubMed","created":"2020-05-20"},{"id":322,"name":"Screening and Druggability Analysis of Some Plant Metabolites Against SARS-CoV-2","author":"Kazi Faizul Azim, Sheikh Rashel Ahmed, Anik Banik, Mostafigur Rahman Khan, Anamika Deb","doi":"10.26434\/chemrxiv.12235949.v1","abstract":"The sudden outbreak of novel corona virus at the end of 2019 has caused a global threat to mankind due to its extreme infection rate and mortality. Despite extensive research, still there is no an approved drug or vaccine to combat SARS-CoV-2 infections. Hence, the study was designed to evaluate some plant-based active compounds for drug candidacy against SARS-CoV-2 by using virtual screening methods and various computational analysis. A total of 27 plant metabolites were screened against SARS-Cov-2 main protease proteins (MPP), Nsp9 RNA binding protein, spike receptor binding domain, spike ecto-domain and HR2 domain using molecular docking approach. Four metabolites i.e. asiatic acid, avicularin, guajaverin and withaferin showed maximum binding affinity with all key proteins in terms of lowest global binding energy. The top candidates were further employed for ADME (absorption, distribution, metabolism, and excretion) analysis to investigate their drug profiles. Results suggest that none of the compounds render any undesirable consequences that could reduce their drug likeness properties. The analysis of toxicity pattern revealed no significant tumorigenic, mutagenic, irritating or reproductive effects by the compounds. However, witheferin was comparatively toxic among the top four candidates with considerable cytotoxicity and immunotoxicity. Most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases hydrolases, phosphatases). Moreover, results of drug similarity prediction identified two approved structural analogs of Asiatic acid from DrugBank, Hydrocortisone (DB00741) (previously used for SARS-CoV-1 and MERS) and Dinoprost-tromethamine (DB01160). In addition, two other biologically active compounds, Mupirocin (DB00410) and Simvastatin (DB00641) could be an alternative choice to witheferin for the treatment of viral infections. The study may pave the way to develop effective medications and preventive measure against SARS-CoV-2 in the future. However, the results were based solely on computational tools and algorithms. Due to the encouraging results, we highly recommend further in vivo trials for the experimental validation of our findings.","type":"Research","database":"ChemRxiv","created":"2020-05-19"},{"id":321,"name":"Identification of Potential Drug Targets and Prediction of the Potential Impact of High Risk Non Synonymous Single Nucleotide Polymorphism in SARS-CoV-2 3C like Proteinase (3CLpro): A Computational Approach","author":"Sahar Elbager, Abdelrahman hamza, Afra M. Al Bkrye, Asia M. Alrashied, Entisar N. M. Ali Hadeel, A. Mohamed, Hazem A. Abubaker, Israa A. Mohamed, Manal A. H. Goda, Mohammed Y. Basher, Naglla F.A Gabir, Safinaz I. Khalil","doi":"10.26434\/chemrxiv.12235181.v1","abstract":"On January 2020, a new coronavirus (officially named SARS-CoV-2) was associated with alarming outbreak of a pneumonia-like illness, which was later named by the WHO as COVID-19, originating from Wuhan City, China. Although many clinical studies involving antiviral and immunomodulatory drug treatments for SARS-CoV-2 all without reported results, no approved drugs have been found to effectively inhibit the virus so far. Full genome sequencing of the virus was done, and uploaded to be freely available for the world scientists to explore. A promising target for SARS-CoV-2 drug design is a chymotrypsin-like cysteine protease (3CLpro), a main protease responsible for the replication and maturation of functional proteins in the life cycle of the SARS coronavirus. Here we aim to explore SARS-CoV-2 3CLpro as possible drug targets based on ligand- protein interactions. In addition, ADME properties of the ligands were also analyzed to predict their drug likeliness. The results revealed Out of 9 ligands, 8 ligands (JFM, X77, RZG, HWH, T8A, 0EN, PEPTIDE and DMS) showed best ADME properties. These findings suggest that these ligands can be used as potential molecules for developing potent inhibitors against SARS-CoV-2 3CLpro, which could be helpful in inhibiting the propagation of the COVID-19. Furthermore, 10 potential amino acids residues were recognized as potential drug binding site (THR25, HIS41, GLY143, SER144, CYS145, MET165, GLU166, GLN189, ASP295 and ARG298). All those amino acid residues were subjected to missense SNP analysis were recognized to affect the structure and function of the protein. These characteristics provide them the promising to be target sites for the fresh generation inhibitors to work with and overcome drug resistance. These findings would be beneficial for the drug development for inhibiting SARS-CoV-2 3CLpro hence assisting the pharmacogenomics effort to manage the infection. of SARS-CoV-2.","type":"Research","database":"ChemRxiv","created":"2020-05-18"},{"id":320,"name":"Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2'-O-Methylation of Viral RNA.","author":"Jos\u00e9 Antonio Encinar, Javier A. Menendez","doi":"10.3390\/v12050525","abstract":"The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2'-O-methyltransferase (2'-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2'-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2'-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16\/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique \"activating surface\" between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed \u22489000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16\/nsp10-drug complexes, we considered their pharmacological overlapping with functional modules of the virus-host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2'-O-methylation.","type":"Research","database":"PubMed","created":"2020-05-18"},{"id":319,"name":"Computational Molecular Docking and Virtual Screening Revealed Promising SARS-CoV-2 Drugs","author":"Maryam Hosseini, Wanqiu Chen Charles Wang","doi":"10.26434\/chemrxiv.12237995.v1","abstract":null,"type":"Research","database":"ChemRxiv","created":"2020-05-18"},{"id":318,"name":"Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized, Controlled Trial","author":"Yan Lou, Lin Liu, Yunqing Qiu","doi":"10.1101\/2020.04.29.20085761","abstract":"Background: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients. Methods: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). Results: Baloxavir showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 \u03bcM comparable to arbidol and lopinavir, but favipiravir did not demonstrate significant antiviral activity up to 100 \u03bcM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. Conclusions: Our findings do not support that adding either baloxavir or favipiravir under the trial dosages to the existing standard treatment.","type":"Research","database":"MedRxiv","created":"2020-05-18"},{"id":317,"name":"Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: an in silico based approach.","author":"Mahanta S, Chowdhury P, Gogoi N, Goswami N, Borah D, Kumar R, Chetia D, Borah P, Buragohain AK, Gogoi B","doi":"10.1080\/07391102.2020.1768902","abstract":"The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was first reported in Wuhan province of China, has become a deadly pandemic causing alarmingly high morbidity and mortality. In the absence of new targeted drugs and vaccines against SARS-CoV-2 at present, the choices for effective treatments are limited. Therefore, considering the exigency of the situation, we focused on identifying the available approved drugs as potential inhibitor against the promising Coronavirus drug target, the Main Protease, using computer-aided methods. We created a library of U. S. Food and Drug Administration approved anti-microbial drugs and virtually screened it against the available crystal structures of Main Protease of the virus. The study revealed that Viomycin showed the highest -CDocker energy after docking at the active site of SARS-CoV-2 Main Protease. It is noteworthy that Viomycin showed higher -CDocker energy as compared to the drugs currently under clinical trial for SARS-CoV-2 treatment <i>viz.<\/i> Ritonavir and Lopinavir. Additionally, Viomycin formed higher number of H-bonds with SARS-CoV-2 Main Protease than its co-crystallised inhibitor compound N3. Molecular dynamics simulation further showed that Viomycin embedded deeply inside the binding pocket and formed robust binding with SARS-CoV-2 Main Protease. Therefore, we propose that Viomycin may act as a potential inhibitor of the Main Protease of SARS-CoV-2. Further optimisations with the drug may support the much-needed rapid response to mitigate the pandemic.","type":"Research","database":"PubMed","created":"2020-05-18"},{"id":316,"name":"Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs","author":"Jeon, Sangeun and Ko, Meehyun and Lee, Jihye and Choi, Inhee and Byun, Soo Young and Park, Soonju and Shum, David and Kim, Seungtaek","doi":"10.1128\/AAC.00819-20","abstract":"Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide - were notable in some respects.","type":"Research","database":"PubMed","created":"2020-05-18"},{"id":314,"name":"The Human Coronavirus Disease COVID-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms.","author":"Alanagreh, L., Alzoughool, F., Atoum, M","doi":"10.3390\/pathogens9050331","abstract":"The emerging coronavirus disease (COVID-19) swept across the world, affecting more than 200 countries and territories. Genomic analysis suggests that the COVID-19 virus originated in bats and transmitted to humans through unknown intermediate hosts in the Wuhan seafood market, China, in December of 2019. This virus belongs to the <i>Betacoronavirus<\/i> group, the same group of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV), and for the similarity, it was named SARS-CoV-2. Given the lack of registered clinical therapies or vaccines, many physicians and scientists are investigating previously used clinical drugs for COVID-19 treatment. In this review, we aim to provide an overview of the CoVs origin, pathogenicity, and genomic structure, with a focus on SARS-CoV-2. Besides, we summarize the recently investigated drugs that constitute an option for COVID-19 treatment.","type":"Review","database":"PubMed","created":"2020-05-15"},{"id":313,"name":"Combined Deep Learning and Molecular Docking Simulations Approach Identifies Potentially Effective FDA Approved Drugs for Repurposing Against SARS-CoV-2","author":"Muhammad U Anwar, Farjad Adnan, Asma Abro, Rayyan A Khan, Asad U Rehman, Muhammad Osama, Saad Javed, Ahmadullah Baig , Muhammad R Shabbir, Muhammad Z Assir","doi":"10.26434\/chemrxiv.12227363.v1","abstract":"The ongoing pandemic of Coronavirus Disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to global public health. Currently no approved drug or vaccine exists against SARS-CoV-2. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, is a time efficient approach to find effective drugs against SARS-CoV-2 in this emergency situation. Both experimental and computational approaches are being employed in drug repurposing with computational approaches becoming increasingly popular and efficient. In this study, we present a robust experimental design combining deep learning with molecular docking experiments to identify most promising candidates from the list of FDA approved drugs that can be repurposed to treat COVID-19. We have employed a deep learning based Drug Target Interaction (DTI) model, called DeepDTA, with few improvements to predict drug-protein binding affinities, represented as KIBA scores, for 2,440 FDA approved and 8,168 investigational drugs against 24 SARS-CoV-2 viral proteins. FDA approved drugs with the highest KIBA scores were selected for molecular docking simulations. We ran docking simulations for 168 selected drugs against 285 total predicted and\/or experimentally proven active sites of all 24 SARS-CoV-2 viral proteins. We used a recently published open source AutoDock based high throughput screening platform virtualflow to reduce the time required to run around 50,000 docking simulations. A list of 49 most promising FDA approved drugs with best consensus KIBA scores and AutoDock vina binding affinity values against selected SARS-CoV-2 viral proteins is generated. Most importantly, anidulafungin, velpatasvir, glecaprevir, rifabutin, procaine penicillin G, tadalafil, riboflavin 5\u2019-monophosphate, flavin adenine dinucleotide, terlipressin, desmopressin, elbasvir, oxatomide, enasidenib, edoxaban and selinexor demonstrate highest predicted inhibitory potential against key SARS-CoV-2 viral proteins.","type":"Research","database":"ChemRxiv","created":"2020-05-14"},{"id":312,"name":"Drug repurposing studies targeting SARS-nCoV2: An ensemble docking approach on drug target 3C-like protease (3CLpro)","author":"Shruti Koulgi, Vinod Jani, Mallikarjunachari Uppuladinne, Uddhavesh Sonavane, A. K. Nath, Hemant Darbari, Rajendra Joshi","doi":"10.1080\/07391102.2020.1792344","abstract":"The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent\r\nbehind this disease is the Severe Acute Respiratory Syndrome \u2013 novel Coronavirus 2 (SARS-\r\nnCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible\r\nfor the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-\r\n19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-\r\nCoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to\r\nbe useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of\r\nmain protease of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug\r\nAdministration (FDA) approved and SWEETLEAD database of drug molecules were screened.\r\nThe apo form of the main protease was simulated for a cumulative of 150 ns and 10 \u03bcs open source\r\nsimulation data was used, to obtain conformations for ensemble docking. The representative\r\nstructures for docking were selected using RMSD-based clustering and Markov State Modeling\r\nanalysis. This ensemble docking approach for main protease helped in exploring the\r\nconformational variation in the drug binding site of the main protease leading to efficient binding\r\nof more relevant drug molecules. The drugs obtained as best hits from the ensemble docking\r\npossessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove\r\nto be useful to treat symptoms exhibited in COVID-19. This in-silico ensemble docking approach\r\nwould support identification of potential candidates for repurposing against COVID-19.\r\n","type":"Research","database":"ChemRxiv","created":"2020-05-14"},{"id":311,"name":"Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication","author":"Wayne Vuong, Muhammad Bashir Khan, Conrad Fischer, Elena Arutyunova, Tess Lamer, Justin Shields, Holly A. Saffran, Ryan T. McKay, Marco J. van Belkum, Michael A. Joyce, Howard S. Young, D. Lorne Tyrrell, John C. Vederas, M. Joanne Lemieux ","doi":"10.1038\/s41467-020-18096-2","abstract":"The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.","type":"Research","database":"BioRxiv","created":"2020-05-13"},{"id":310,"name":"Drug reaction with eosinophilia and systemic symptoms syndrome to hydroxychloroquine, an old drug in the spotlight.","author":"Grandolfo M, Romita P, Bonamonte D, Cazzato G, Hansel K, Stingeni L, Conforti  C, Giuffrida R, Foti C","doi":"10.1111\/dth.13499","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-12"},{"id":309,"name":"CNS penetration of potential anti-COVID-19 drugs","author":"Richardson PJ, Ottaviani S, Prelle A, Stebbing J, Casalini G, Corbellino M","doi":"10.1007\/s00415-020-09866-5","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-12"},{"id":308,"name":"FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication","author":"Lobo-Galo N, Terrazas-L\u00f3pez M, Mart\u00ednez-Mart\u00ednez A, D\u00edaz-S\u00e1nchez \u00c1G","doi":"10.1080\/07391102.2020.1764393","abstract":"Emergent novel SARS-CoV-2 is responsible for the current pandemic outbreak of severe acute respiratory syndrome with high mortality among the symptomatic population worldwide. Given the absence of a current vaccine or specific antiviral treatment, it is urgent to search for FDA-approved drugs that can potentially inhibit essential viral enzymes. The inhibition of 3CLpro has potential medical application, due to the fact that it is required for processing of the first translated replicase polyproteins into a series of native proteins, which are essential for viral replication in the host cell. We employed an in silico approach to test if disulfiram, as well as its metabolites, and captopril could be used as potential antiviral drugs against COVID-19. We provide data on the potential covalent interaction of disulfiram and its metabolites with the substrate binding subsite of 3CLpro and propose a possible mechanism for the irreversible protease inactivation thought the reaction of the aforementioned compounds with the Cys145. Although, captopril is shown to be a potential ligand of 3CLpro, it is not recommended anti-COVID-19 therapy, due to the fact that it can induce the expression of the viral cellular receptor such as, angiotensin-converting enzyme ACE-2, and thus, making the patient potentially more susceptible to infection. On the other hand, disulfiram, an alcoholism-averting drug, has been previously proposed as an antimicrobial and anti-SARS and MERS agent, safe to use even at higher doses with low side effects, it is recommended to be tested for control of SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2020-05-12"},{"id":307,"name":"Development and validation of a UHPLC-MS\/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2\/COVID-19 and Ebola virus disease.","author":"Avataneo V, de Nicol\u00f2 A, Cusato J, Antonucci M, Manca A, Palermiti A, Waitt C, Walimbwa S, Lamorde M, di Perri G, D'Avolio A","doi":"10.1093\/jac\/dkaa152","abstract":"BACKGROUND:\r\n\r\nRemdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2\u2009h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24\u2009h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.\r\nOBJECTIVES:\r\n\r\nThe validation of a reliable UHPLC-MS\/MS method for remdesivir and GS-441524 quantification in human plasma.\r\nMETHODS:\r\n\r\nRemdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS\/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8\u2009\u03bcm, 2.1\u205f\u00d7\u205f50\u2009mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.\r\nRESULTS:\r\n\r\nAnalyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.\r\nCONCLUSIONS:\r\n\r\nThis method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.","type":"Research","database":"PubMed","created":"2020-05-12"},{"id":306,"name":"Covid-19: Remdesivir is helpful but not a wonder drug, say researchers.","author":"Mahase E","doi":"10.1136\/bmj.m1798","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-12"},{"id":305,"name":"Non-steroidal anti-inflammatory treatment during covid-19: friend or foe?","author":"Monti S, Montecucco C","doi":"10.1136\/annrheumdis-2020-217638","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-12"},{"id":304,"name":"Challenges in Drug Development Posed by the COVID-19 Pandemic: An Opportunity for Clinical Pharmacology.","author":"Karthik Venkatakrishnan,  Oezkan Yalkinoglu,  Jennifer Q. Dong,  Lisa J. Benincosa","doi":"10.1002\/cpt.1879","abstract":"The unprecedented challenges posed by the COVID\u201019 pandemic highlight the urgency for applying clinical pharmacology and model\u2010informed drug development in (i) dosage optimization for COVID\u201019 therapies, (ii) approaching therapeutic dilemmas in clinical trial settings, and (iii) maximizing value of information from impacted non\u2010COVID\u201019 trials. More than ever, we have a responsibility for adaptive evidence synthesis with a Totality of Evidence mindset in this race against time across biomedical research, clinical practice, drug development and regulation.","type":"Comment","database":"PubMed","created":"2020-05-11"},{"id":303,"name":"Cutaneous S\u0131de\u2010Effects of the Potent\u0131al Cov\u0131d\u201019 Drugs","author":"\u00dcmit T\u00fcrsen, Belma T\u00fcrsen, Torello Lotti","doi":"10.1111\/dth.13476","abstract":"COVID\u201019 disease, is a highly contagious and a particularly popular problem in all countries. A variety of repurposed drugs and investigational drugs such as remdesivir, chloroquine, hydroxychloroquine, ritonavir, lopinavir, inteferon\u2010beta and the other potential drugs have been studied for COVID19 treatment. We reviewed the potential dermatological side\u2010effects of these drugs.","type":"Research","database":"PubMed","created":"2020-05-11"},{"id":302,"name":"Off\u2010target ACE2 ligands: possible therapeutic option for CoVid\u201019?","author":"Simone Brogi, Vincenzo Calderone","doi":"10.1111\/bcp.14343","abstract":"No abstract available.","type":"Comment","database":"PubMed","created":"2020-05-11"},{"id":301,"name":"A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID\u201019","author":"Sadakat Chowdhury, Jay Rathod, Joel Gernsheimer","doi":"10.1111\/acem.14005","abstract":"Background\r\nThe emergence of SARS\u2010CoV\u20102 has presented clinicians with a difficult therapeutic dilemma. With supportive care as the current mainstay of treatment, the fatality rate of COVID\u201019 is 6.9%. There are currently several trials assessing the efficacy of different antivirals as treatment. Of these, Chloroquine (CQ) and derivative, Hydroxychloroquine (HCQ), have garnered the most attention.\r\n\r\nMethods\r\nIn this study, the literature currently available on CQ and HCQ as treatment of COVID\u201019 was surveyed using EMBASE, PubMed, Cochrane Librar, MedRxiv and 1 clinical trial registry. Upon gathering published and preprint trials, risk of bias was assessed using Cochrane Risk of Bias Tool 2.0.\r\n\r\nResults\r\nThere are currently 7 completed clinical trials and 29 registered clinical trials focusing on HCQ or CQ as a therapeutic avenue for COVID\u201019. Of these, 5\/7 trials have shown favorable outcomes for patients using CQ or HCQ and 2\/7 have shown no change compared to control. However, all 7 trials carried varying degrees of bias and poor study design.\r\n\r\nConclusion\r\nThere is currently not enough data available to support the routine use of HCQ and CQ as therapies for COVID\u201019. Pending further results from more extensive studies with more stringent study parameters, clinicians should defer from routine use of HCQ and CQ. There are several clinical trials currently underway with results expected soon.","type":"Review","database":"PubMed","created":"2020-05-11"},{"id":300,"name":"Methods of An Open-Label Proof-Of-Concept Trial of Intravenous Valproic Acid for Severe COVID-19","author":"Erwin Chiquete, Liz Toapanta-Yanchapaxi, Carlos Cantu-Brito","doi":"10.1101\/2020.04.26.20079988","abstract":"Background: Coronavirus disease 2019 (COVID-19) is the systemic entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may cause death through severe atypical pneumonia and acute lung injury. Valproic acid (VPA) has shown anti-inflammatory activity and mild intrinsic antiviral effect. These properties warrant the study of VPA as a possible active treatment in persons with severe COVID-19. Methods: Consecutive adult patients needing invasive mechanical ventilation (IMV) will be given intravenous (i.v.) VPA at a starting dose of 20 mg\/kg\/day and up to 60\/kg\/day (in 60 min i.v. infusions in 250 mL normal saline) as needed to reach plasma VPA concentrations of 50-100 mcg\/mL (measured every 72 h). These patients will be followed-up for 10 days for the primary outcome and for a further period of 30 days after treatment completion for the secondary outcome of recurrence. The primary study outcome is the reduction in the case fatality rate of at least 50% after 10 days of treatment (as compared with natural history). Secondary outcomes are the reduction of length of stay (LOS) of at least 50%, as well as COVID-19 recurrence at 30-day follow-up. The most important safety outcomes are acute liver failure, acute pancreatitis, and thrombocytopenia. Conclusion: Although long-term adverse effects and even pro-inflammatory consequences have been reported with the chronic use of VPA, given the urgent need for a drug against COVID-19 to shorten the high mortality and LOS, the study of VPA is justified from a scientific standpoint.","type":"Other","database":"PubMed","created":"2020-05-11"},{"id":299,"name":"Favipiravir for treating novel coronavirus (COVID-19) patients: protocol for a systematic review and meta-analysis of controlled trials","author":"Morteza Arab-Zozani, Soheil Hassanipour, DJavad GHoddoosi-Nejad","doi":"https:\/\/doi.org\/10.1101\/2020.04.27.20081471","abstract":"An outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was reported in Wuhan, China in mid-December 2019, and declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Due to the unknown nature of the disease and the lack of specific drugs, several potential treatments were used for patients. This systematic review and meta-analysis will evaluate studies of the effects of Favipiravir in COVID-19 pneumonia. Methods and analysis We will search electronic databases including LitCovid hub, PubMed, Scopus, ISI web of Sciences, Cochrane, and Embase using keywords related to COVID-19 and Favipiravir. We will search the reference lists of all included studies and reviews. We will also search for clinical trial registries, such as clinicaltrial.gov for the ongoing clinical trials. Two investigators (MAZ and SH) will independently screen titles, abstracts, and full-text of included studies based on eligibility criteria. These investigators will also independently extract data and appraise the quality of studies. All potential discrepancies will be resolved through consultation with the third reviewer. Data synthesis will be conducted using the Review Manager software (version 5.3) or CMA (version 2). Statistical heterogeneity will be assessed using a standard I2 test. A funnel plot, Egger test, and Begg test will be used for asymmetry to explore possible publication bias. Ethics and dissemination The findings of this systematic review with proportional meta-analysis will help to identify the safety and efficacy of Favipiravir for COVID-19 patients. Knowledge gained from this research will also assist physicians in selecting better treatment options and developing a guideline in this field.","type":"Review","database":"MedRxiv","created":"2020-05-11"},{"id":298,"name":"Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs","author":"Ujjwal Neogi, Kyle J. Hill, Anoop T Ambikan, Xiao Heng, Thomas P. Quinn, Siddappa N. Byrareddy, Anders S\u00f6nnerborg, Stefan G. Sarafianos, Kamal Singh","doi":"10.3390\/pathogens9050320","abstract":"Coronaviruses (CoVs) are positive-stranded RNA viruses that infect humans and animals.\r\nInfection by CoVs such as HCoV-229E, -NL63, -OC43 and -HKU1 leads to the common cold, short\r\nlasting rhinitis, cough, sore throat and fever. However, CoVs such as Severe Acute Respiratory\r\nSyndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERSCoV), and the newest SARS-CoV-2 (the causative agent of COVID-19) lead to severe and deadly\r\ndiseases with mortality rates ranging between ~1 to 35% depending on factors such as age and preexisting conditions. Despite continuous global health threats to humans, there are no approved\r\nvaccines or drugs targeting human CoVs, and the recent outbreak of COVID-19 emphasizes an\r\nurgent need for therapeutic interventions. Using computational and bioinformatics tools, here we\r\npresent the feasibility of reported broad-spectrum RNA polymerase inhibitors as anti- SARS-CoV2 drugs targeting its main RNA polymerase, suggesting that investigational and approved\r\nnucleoside RNA polymerase inhibitors have potential as anti-SARS-CoV-2 drugs. However, we note\r\nthat it is also possible for SARS-CoV-2 to evolve and acquire drug resistance mutations against these\r\nnucleoside inhibitors.","type":"Research","database":"PubMed","created":"2020-05-10"},{"id":297,"name":"Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target","author":"arun kumar, Sharanya C.S, Abhithaj J, Dileep Francis, Sadasivan C","doi":"10.26434\/chemrxiv.12199610.v1","abstract":"Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.","type":"Research","database":"ChemRxiv","created":"2020-05-07"},{"id":296,"name":"In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA dependent RNA polymerase (RdRp) and Necessary Proteases","author":"Trinath Chowdhury, Gourisankar Roymahapatra, Santi M Mandal","doi":"10.26434\/chemrxiv.12200495.v1","abstract":"The work demonstrate screening of several arsenical compounds against RdRp of coronavirus. The study implies out of all arsenical compounds, darinaparsin shows its most effective results based on in silico docking analysis. This study also confirmed the significant interaction between the active site of viral replicase protein, endoribonuclease protein and different proteases with darinaparsin.","type":"Research","database":"ChemRxiv","created":"2020-05-07"},{"id":295,"name":"Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study","author":"Ancy Iruthayaraj, Sivanandam Magudeeswaran, Kumaradhas Poomani","doi":"10.26434\/chemrxiv.12204668.v1","abstract":"Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (Mpro) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (Mpro). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 Mpro. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of Mpro enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of Mpro and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal\/mol, respectively. This in silico study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 Mpro enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.","type":"Research","database":"ChemRxiv","created":"2020-05-07"},{"id":294,"name":"Evaluation of 19 antiviral drugs against SARS-CoV-2 Infection","author":"Shufeng Liu, Christopher Z. Lien, Prabhuanand Selvaraj, Tony T. Wang","doi":"10.1101\/2020.04.29.067983","abstract":"The global pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV) has prompted multiple clinical trials to jumpstart search for anti-SARS-CoV-2 therapies from existing drugs, including those with reported in vitro efficacies as well as those ones that are not known to inhibit SARS-CoV-2, such a Ritonavir\/lopinavir and Favilavir. Here we report that after screening 19 antiviral drugs that are either in clinical trials or with proposed activity against SARS-CoV-2, remdesivir was the most effective. Chloroquine only effectively protected virus-induced cytopathic effect at around 30 \u00b5M with a therapeutic index of 1.5. Our findings also show that velpatasvir, ledipasvir, litonavir, lopinavir, favilavir, sofosbuvir do not have direct antiviral effect.","type":"Research","database":"BioRxiv","created":"2020-05-07"},{"id":293,"name":"Activity profiling of SARS-CoV-2-PLpro protease provides structural framework for anti-COVID-19 drug design","author":"Wioletta Rut, Mikolaj Zmudzinski, Zongyang Lyu, Digant Nayak, Scott J. Snipas, Miklos Bekes, Tony T. Huang, Shaun K. Olsen, Marcin Drag","doi":"10.1101\/2020.04.29.068890","abstract":"In December 2019, the first cases of a novel coronavirus infection causing COVID-19 were diagnosed in Wuhan, China. Viral Papain-Like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs which would be facilitated by an understanding of its substrate specificity. Here, we used a combinatorial substrate library containing natural and a wide variety of nonproteinogenic amino acids and performed comprehensive activity profiling of SARS-CoV-2-PLpro. We found that the P2 site of SARS-CoV-2-PLpro is highly specific for Gly, the P3 site exhibits a high degree of promiscuity, and the P4 site exhibits a preference for amino acids with hydrophobic side chains. We also demonstrate that SARS-CoV-2-PLpro harbors deubiquitinating activity. Both the substrate binding profile and deubiquitinating activity are shared with the highly related SARS-CoV-PLpro which harbors near identical S4-S2 binding pockets. On the scaffold of best hits from positional scanning we have designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro variants versus other proteases. Altogether this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repositioning.","type":"Research","database":"BioRxiv","created":"2020-05-07"},{"id":292,"name":"Hopes rise for coronavirus drug remdesivir","author":"Ledford H","doi":"10.1038\/d41586-020-01295-8","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-07"},{"id":291,"name":"RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials","author":"Wilkinson E","doi":"10.1136\/bmj.m1626","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-07"},{"id":290,"name":"An independent appraisal and re-analysis of hydroxychloroquine treatment trial for COVID-19","author":"Intson K, Kumar S, Botta A, Neckles R, Leung C, Jawaid A","doi":"10.4414\/smw.2020.20262","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-07"},{"id":289,"name":"Effects of novel coronavirus therapeutic drugs on cardiovascular system","author":"Xie SY, Deng W, Tang QZ","doi":"10.3760\/cma.j.cn112148-20200404-00279","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-07"},{"id":288,"name":"Anti COVID-19 Drugs: Need for More Clinical Evidence and Global Action","author":"Khan Z, Karata\u015f Y, Rahman H","doi":"10.1007\/s12325-020-01351-9","abstract":"The World Health Organization (WHO) called the outbreak of coronavirus infectious disease-2019 (COVID-19) a \"Public Health Emergency of International Concern\" (PHEIC). According to the WHO, Centers for Disease Control and Prevention (CDC), and the US Food and Drug Administration (FDA), currently there are no medicines or vaccines that have been claimed to be useful in the prevention or treatment of COVID-19. Several existing antiviral drugs, previously developed or used as treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), human immunodeficiency virus (HIV), and malaria, are being investigated as COVID-19 treatments and some of them are being used in clinical trials. According to the CDC and Chinese treatment guidelines for COVID-19, chloroquine, hydroxychloroquine, lopinavir\/ritonavir, and one of the investigational agents (remdesivir) are recommended in critically ill older patients. The use of other potential drugs reported in different studies may be considered if treatment with first-line drugs is ineffective. There are currently no complete data available from large randomized clinical trials (RCTs) to provide clinical guidance on the use, dosing, or duration to validate the effective role, safety profile, and adverse effects of all of the trial drugs for prophylaxis or treatment of COVID-19. Until now, it is still unclear which drug can successfully fight against the disease. Therefore, for the better safety of patients with COVID-19, further clinical trials and large randomized controlled studies are needed to validate the effective role, safety profile, and adverse effects of all the potential drugs. Such a measure requires action at the global level.","type":"Comment","database":"PubMed","created":"2020-05-07"},{"id":287,"name":"Drugs that aggravate the course of COVID-19\u2005: really\u2005?","author":"Rothuizen LE, Livio F, Buclin T","doi":"10.1111\/ajt.15967","abstract":"The safety of NSAIDs, corticosteroids and renin-angiotensin inhibitors in COVID-19 is challenged. NSAIDs may interfere with the defense process against viral infection and are best avoided. Systemic corticosteroids have not shown benefit in viral infection, including other coronavirus; thus they should be avoided, unless prescribed for another indication. The benefit-risk ratio is however clearly in favor of continuing inhaled corticosteroids in patients with asthma or COPD. ACE inhibitors and sartans upregulate the expression of angiotensin-converting enzyme 2 (ACE2), the pulmonary receptor for SARS-CoV-2. Any possible clinical impact of these treatments on COVID-19 infection remains to be clarified; in the meantime, they should be continued.","type":"Comment","database":"PubMed","created":"2020-05-07"},{"id":286,"name":"Will the antimalarial drug take over to combat COVID-19?","author":"Sivabakya TK, Srinivas G","doi":"10.1007\/s10389-020-01293-0","abstract":"Background:\r\n\r\nChina has been fighting the epidemic of pneumonia-like diseases first detected for over a month in the city of Wuhan in December 2019. The disease epidemic is caused by a novel coronavirus, called COVID-19, which has now infected more than 700,000 people worldwide. With a death toll approaching that of China's SARS-CoV outbreak in 2002 and 2003, 2019-nCoV has contributed to an international emergency in public health, placing all health organizations on high alert. Such large numbers of infected and deceased people require an urgent need for reliable, inexpensive, and cheap drugs to control and reduce the outbreak.\r\nObjective:\r\n\r\nTo systematically review and evaluate the pattern of COVID-19 and the treatment plans.\r\nMethods:\r\n\r\nThis systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The articles were searched from databases like PubMed, the Cochrane Library, ScienceDirect, and the Health Research and Development Information Network (HERDIN) combining MeSH and free-text terms.\r\nResults:\r\n\r\nThis analysis highlights the agent of COVID-19 and the possible transmission. The current research taking place to overcome this complex disease and the urgent need to develop improved therapeutics are also discussed.\r\nConclusion:\r\n\r\nHerein, we present an epidemiological overview of the currently available information on the treatment claimed to have helped to bring the situation under control.","type":"Review","database":"PubMed","created":"2020-05-07"},{"id":285,"name":"Stilbene-based Natural Compounds as Promising Drug Candidates against COVID-19","author":"Wahedi HM, Ahmad S, Abbasi SW","doi":"10.1080\/07391102.2020.1762743","abstract":"The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a great threat to public health. Currently, no potent medicine is available to treat COVID-19. Quest for new drugs especially from natural plant sources is an area of immense potential. The current study aimed to repurpose stilbenoid analogs, reported for some other biological activities, against SARS-CoV-2 spike protein and human ACE2 receptor complex for their affinity and stability using molecular dynamics simulation and binding free energy analysis based on molecular docking. Four compounds in total were probed for their binding affinity using molecular docking. All of the compounds showed good affinity (> -7\u2009kcal\/mol). However, fifty nanoseconds molecular dynamic simulation in aqueous solution revealed highly stable bound conformation of resveratrol to the viral protein: ACE2 receptor complex. Net free energy of binding using MM-PBSA also affirmed the stability of the resveratrol-protein complex. Based on the results, we report that stilbene based compounds in general and resveratrol, in particular, can be promising anti-COVID-19 drug candidates acting through disruption of the spike protein. Our findings in this study are promising and call for further in vitro and in vivo testing of stiblenoids, especially resveratrol against the COVID-19.","type":"Research","database":"PubMed","created":"2020-05-07"},{"id":284,"name":"Metformin and COVID-19: A novel deal of an Old Drug.","author":"El-Arabey AA, Abdalla M","doi":"10.1002\/jmv.25958","abstract":"In 2002, China witnessed the emergence of a severe acute respiratory disease \r\ncaused by coronavirus SARS-CoV. Ten years later in 2012 a new version of the \r\nvirus appeared in the Middle East known as Middle East Respiratory Syndrome \r\nCoronavirus MERS-CoV. At the end of 2019, the Chinese Center for Disease \r\nControl and Prevention (China CDC) recorded a pneumonia of unknown causes. \r\nEpidemiologically, the pneumonia was linked to a wet animal and seafood \r\nwholesale market in Wuhan, Hubei Province, China, later Known by COVID-19. \r\nThe COVID-19 is a global pandemic infectious disease caused by severe acute \r\nrespiratory syndrome coronavirus 2 (SARS-CoV-2). Till now the total number of \r\nconfirmed cases is 2,709,483 in over 225 countries around the world. A recent \r\nreport indicates that obesity may responsible for increasing the mortality of \r\nCOVID-19 in Italy rather than in China. Here we would like to shed light on a \r\nnew suggestion to decrease the mortality rate of COVID-19.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":283,"name":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","author":"Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Huettenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ,  Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, ","doi":"10.1038\/s41586-020-2286-9","abstract":"The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.","type":"Research","database":"PubMed","created":"2020-05-05"},{"id":282,"name":"Perspectives for the use of therapeutic Botulinum toxin as a multifaceted candidate drug to attenuate COVID-19","author":"Kandasamy M","doi":"10.1016\/j.medidd.2020.100042","abstract":"The recent outbreak of coronavirus disease (COVID-19) resulting from a distinctive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to evolve in many countries and pose life-threatening clinical issues to global public health. While the lungs are the primary target for the SARS-CoV-2-mediated pathological consequence, SARS-CoV-2 appear to invade the brain and cause neurological deficits. In the later stage, COVID-19 can progress to pneumonia, acute respiratory failure, neurological deficits and multi-organ dysfunctions leading to death. Though a significant portion of SARS-CoV-2 infected individuals has been recovering from pathological symptoms, the impact of the COVID-19 on the structural and functional properties of the lungs, heart, brain and other organs at the post-recovery state remains unknown. Presently, there is an urgent need for a remedial measure to combat this devastating COVID-19. Botulinum toxins (BoNTs) are potent neurotoxins that can induce paralysis of muscle and acute respiratory arrest in human. However, a mild dose of the purified form of BoNT has been known to attenuate chronic cough, dyspnoea, pneumonia, acute respiratory failure, abnormal circulation, cardiac defects and various neurological deficits that have been recognised as the prominent clinical symptoms of COVID-19. Considering the fact, this review article provides 1) an overview on the SARS-CoV-2 mediated pathological impact on the lungs, heart and brain, 2) signifies the therapeutic uses of BoNTs against pulmonary failure, cardiac arrest and neurological deficits, and 3) emphasize the rationality for the possible use of BoNT to prevent SARS-CoV-2 infection and manage COVID-19.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":281,"name":"A Novel Protein Drug, Novaferon, as the Potential Antiviral Drug for COVID-19","author":"Fang Zheng, Yanwen Zhou, Zhiguo Zhou, Fei Ye, Baoying Huang, Yaxiong Huang, Jing Ma, Qi Zuo, Xin Tan, Jun Xie, Peihua Niu, Wenlong Wang, Yun Xu, Feng Peng, Ning Zhou, Chunlin Cai, Wei Tang, Xinqiang Xiao, Yi Li, Zhiguang Zhou, Zhiguang Zhou, Yongfang Jiang, Yuanlin Xie, Wenjie Tan, Guozhong Gong","doi":"10.1101\/2020.04.24.20077735","abstract":"Background Novaferon, a novel protein drug approved for the treatment of chronic hepatitis B in China, exhibits potent antiviral activities. We aimed to determine the anti-SARS-CoV-2 effects of Novaferon in vitro, and conducted a randomized, open-label, parallel group study to explore the antiviral effects of Novaferon for COVID-19. Methods In laboratory, the inhibition of Novaferon on viral replication in cells infected with SARS-CoV-2, and on SARS-CoV-2 entry into healthy cells was determined. Antiviral effects of Novaferon were evaluated in COVID-19 patients with treatment of Novaferon, Novaferon plus Lopinavir\/Ritonavir, or Lopinavir\/Ritonavir. The primary endpoint was the SARS-CoV-2 clearance rates on day 6 of treatment, and the secondary endpoint was the time to the SARS-CoV-2 clearance in COVID-19 patients Results Novaferon inhibited the viral replication in infected cells (EC50=1.02 ng\/ml), and protected healthy cells from SARS-CoV-2 infection (EC50=0.1 ng\/ml). Results from the 89 enrolled COVID-19 patients showed that both Novaferon and Novaferon plus Lopinavir\/Ritonavir groups had significantly higher SARS-CoV-2 clearance rates on day 6 than the Lopinavir\/Ritonavir group (50.0% vs.24.1%, p = 0.0400, and 60.0% vs.24.1%, p = 0.0053). Median time to SARS-CoV-2 clearance were 6 days, 6 days, and 9 days for three groups respectively, suggesting a 3-dayreduction of time to SARS-CoV-2 clearance in both Novaferon and Novaferon plus Lopinavir\/Ritonavir groups compared with Lopinavir\/Ritonavir group. Conclusions Novaferon exhibited anti-SARS-CoV-2 effects in vitro and in COVID-19 patients. These data justified the further evaluation of Novaferon.","type":"Research","database":"MedRxiv","created":"2020-05-05"},{"id":280,"name":"Antibody testing will enhance the power and accuracy of COVID-19-prevention trials","author":"Lipsitch M, Kahn R, Mina MJ","doi":"10.1038\/s41591-020-0887-3","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":279,"name":"Debate on Drugs That May Aggravate COVID-19","author":"Giavina-Bianchi P, Aun MV, Agondi RC, Kalil J","doi":"10.1016\/j.jaip.2020.04.037","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":278,"name":"Discontinuation of antiviral drugs may be the reason for recovered COVID-19 patients testing positive again.","author":"Wu F, Zhang W, Zhang L, Wang D, Wan Y","doi":"10.12968\/hmed.2020.0156","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":277,"name":"Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target - A Perspective.","author":"Magrone T, Magrone M, Jirillo E","doi":"10.2174\/1871530320666200427112902","abstract":"Coronaviruses (CoVs) possess an enveloped, single, positive-stranded RNA genome which encodes for four membrane proteins, namely spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins 3-5 [1]. With regard to pathogenicity, S proteins are essential for viral entry into host cells [2, 3]. SARS-CoV binds to the angiotensin-converting enzyme (ACE)2 which is present on nonimmune cells, such as respiratory and intestinal epithelial cells, endothelial cells, kidney cells (renal tubules) and cerebral neurons and immune cells, such as alveolar monocytes\/macrophages [4-6]. Of note, CD209L or liver\/lymph node special intercellular adhesion molecule-3-grabbing non-integrin (SIGN) and dendritic cell (DC)-SIGN are alternative receptors for SARS-CoV but with lower affinity [7]. In the case of MERS-CoV, S proteins bind to the host cell receptor dipeptidyl peptidase 4 (DPP4 or CD26) which is broadly expressed on intestinal, alveolar, renal, hepatic and prostate cells as well as on activated leukocytes [8]. Then, viruses replicate in target cells with release of mature virions, which, in turn, invade new target cells [9]. Evidence has been provided that SARSCoV proteins are cleaved into two subunits, S1 and S2, respectively, and the amino acids 318-510 of the S1 represent the receptor-binding domain (RBD) which binds to ACE2 [10, 11]. Quite importantly, in the context of RBD there is the receptor-binding motif (RBM) (amino acids 424- 494), which accounts for complete binding to ACE2 [11]. Moreover, by means of two residues at positions 479 and 487 RBD allows virus progression and tropism [10, 11]. In the case of MERSCoV, its RBM binds to DPP4 with residues 484-567, thus, suggesting that its RBD differs from that of SARS-CoV [12, 13]. In a very recent paper, Wan and associates [14] have investigated the receptor recognition by COVID-19 (a new term to indicate the 2019-nCoV in Wuhan) on the bases of structural studies. In this respect, the sequence of COVID-19 RBM is similar to that of SARSCoV, thus, implicating that ACE2 may represent the binding receptors for COVID-19. Furthermore, gln493 residue of COVID-19 RBM seems to allow interaction with human ACE2, thus, suggesting the ability of this virus to infect human cells. According, to Wan and associates structural analysis [14], COVID-19 binds to human ACE2 with a lesser efficiency than human SARS-CoV (2002) but with higher affinity than human SARS-CoV (2003). Furthermore, same authors predicted that a single mutation at the 501 position may enhance the COVID-19 RBD binding capacity to human ACE2 and this evolution should be monitored in infected patients [14]. These predictive findings by Wan and associates [14] are confirmed by two contemporary studies by Letko and Muster [15] and Peng and associates [16]. In particular, the report by Peng and associates [16], points out the possible origin of COVID-19 from bats [16]. From a pathogenic point of view, evidence has been provided that binding of S2 to ACE2 receptor leads to its down-regulation with subsequent lung damage in the course of SARS-CoV infection [17]. Down-regulation of ACE2 causes excessive production of angiotensin (ANG) II by the related enzyme ACE with stimulation of ANG type 1a receptor (AT1R) and enhanced lung vascular permeability [18]. In particular, same authors have reported that recombinant ACE2 could attenuate severe acute lung injury in mice [18]. Moreover, Battle and associates [19] also proposed to use already available recombinant ACE2 for intercepting COVID-19 and attenuating infection. In the previous paragraphs, the presence of ACE2 on immune cells has been pointed out and, by analogy to epithelial cells, this receptor may also be down-regulated following viral entry. Therefore, in CoV-infected animal models and in infected humans further investigations are required to clarify a possible reduced expression of ACE2 on immune cells. In fact, in the course of SARS-CoV infection, a number of immune disorders have been detected. Three reports have demonstrated the ability of CoV to inhibit interferon (IFN)-\uf062 production in the course of SARS acting as IFN antagonist [20-22]. In senescent Balb\/c mice, depletion of T lymphocytes is associated to more severe interstitial pneumonitis and delayed clearance of SARS-CoV, thus, suggesting a protective role played by these cells [23]. In this connection, both SARS-CoV and MERS-CoV have been shown to induce T cell apoptosis, thus, aggravating the clinical course of disease [24, 25]. Quite interestingly, memory CD8+ T cells specific for SARS-CoV M and N proteins have been detected up to 11 years post-infection [26]. As far as humoral immune responsiveness is concerned, evidence has been provided that S1 subunit from MERS-CoV is highly immunogenic in mice [27]. Moreover, monoclonal antibodies have been shown to be highly neutralizing against MERS-CoV replication and endowed with post exposure effectiveness in susceptible mice [28, 29]. Human neutralizing antibodies have also been isolated from a recovered patient, thus, suggesting the role of humoral immunity in the control of the persistence of CoV in the host [30]. In particular, IgG response occurs early in infection and its prolonged production may serve for virus clearance during recovery also in view of the absence of viremia in convalescent sera from SARS patients [31]. According to current literature, severity of COVID-19 infection correlates with lymphopenia and patients who died from COVID-19 had lower lymphocyte counts when compared to survivors [32, 33]. These data suggest that lymphocyte-mediated anti-viral activity is poorly effective against COVID-19. Despite lymphopenia, evidence for an exaggerate release of proinflammatory cytokines [interleukin (IL)-1 and IL-6] has been reported in the course acute respiratory syndrome in COVID19 infected patients, thus, aggravating the clinical course of disease [34]. As recently reported, during COVID-19 pandemic in both Italy and China higher frequency of fatalities have been observed in the frail elderly population with previous comorbidities [35]. It is well known that decline of immunity occurs in ageing and, therefore, COVID-19 may gain easier access to the respiratory tract in frail elderly patients [36]. There is evidence that ACE2 protects from severe acute lung failure and operates as a negative regulator of the renin-angiotensin system (RAS) [18, 37]. It is well known that ANG II via activation of the AT1R promotes detrimental effects on the host, such as, vasoconstriction, reactive oxygen species generation, inflammation and matrix remodelling [38]. ACE2 counterbalances the noxious effects exhibited by ANG II and AT1R via activation of AT2R which arrests cell growth, inflammation and fibrosis [39]. In this framework, Gurwitz [40] proposed to use AT1R blockers, such as losartan, as a potential treatment of COVID-19 infection. In fact, losartan as well as olmesartan, used for treating hypertension in patients, were able to increase ACE2 expression after 28 days treatment of rats with myocardial infarction [41]. Then, Gurwitz suggests to evaluate severity of symptoms in COVID-19 infected patients under previous chronic treatment with AT1R blockers in comparison to COVID-19 infected patients who did not take AT1R blockers [40]. Quite interestingly, 75% of aged COVID-19 infected patients admitted to Italian hospitals had hypertension [unpublished data]. However, the putative effects of ACE-2 down-regulation on the cardiovascular system in the course of COVID-19 pandemic need more intensive studies. Taken together, these evidences suggest that CoV-induced down-regulation of ACE2 activates RAS with collateral damage to organs, such as lungs, in the course of SARS-related pneumonia. Then, putative therapeutic measures aimed at increasing ACE2 levels on respiratory epithelial cells should be taken into serious consideration. Quite interestingly, over the past few years, three key papers have demonstrated the ability of a polyphenol, resveratrol (RES), to experimentally deactivate the RAS system in maternal and post-weaning high fat diet, arterial ageing and high fat diet, respectively [42-44]. In all these experimental models, RES led to an increase of ACE2 with reduction of organ damage, such as liver steatosis and aorta media thickness and decrease of adipose tissue mass, respectively. As far as the mechanism of action of RES is concerned, this polyphenol is able to activate sirtuin (Sirt)1 [45-47]. In turn, Sirt1 down-regulates AT1R expression via ACE2 up-regulation [43, 48]. Of importance, Lin and associates [48] have demonstrated the ability of RES to in vitro inhibit MERS-CoV infection of Vero E6 cells, thus, prolonging cell survival in virtue of an anti-apoptotic mechanism. These findings suggest a direct antiviral effect exerted by RES. It would be very interestingly to evaluate the direct effects of RES on COVID-19, in vitro. The data above discussed strongly suggest, that RES, as an activators of ACE2, should be investigated in animal models of CoV-induced severe pneumonia, also taking into account the antioxidant, anti-inflammatory and immunomodulating effects exerted by polyphenols [49]. Then, successful animal studies may pave the way for RES-based human trials in COVID-infected patients. Note added in proof During the reviewing process of this perspective other related papers have been published. Hanff and associates [50] have discussed the possible association between COVID-19-associated cardiovascular mortality and dysregulation of the Renin Angiotensin System (RAS). From a pharmacologic point of view, RAS inhibition leads to upregulation of ACE2, thus, attenuating acute respiratory syndrome and myocarditis in COVID-19-infected patients. Conversely, increase in ACE2 expression may facilitate the access into the host of COVID-19, thus, aggravating the clinical picture. Such a dilemma would be solved by clinical trials based on RAS blockade or initiation and monitoring related effects. Contemporarily, Danser and associates [51] claim that there is no evidence to stop RAS blockers in the course of COVID-19 infection. In fact, there are no available data which support that ACE inhibitors or ANG II type I receptor blockers increase COVID-19 infection via its binding to ACE2. Finally, Kuster and associates [52] write that there are no data on the strict relationship between ACE2 activity and SARS-CoV2 mortality. Moreover, in the SARSCoV2, cells expressing ACE2 were not attacked by the virus, while cells lacking ACE2 were bound by the SARS-CoV2 virus [53]. These findings suggest that also in the case of RES effects on COVID-19 infection, the dual role of ACE2 should be taken into serious consideration.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":276,"name":"ACE2 correlated with immune infiltration serves as a prognostic biomarker in endometrial carcinoma and renal papillary cell carcinoma: implication for COVID-19","author":"Yang J, Li H, Hu S, Zhou Y","doi":"10.18632\/aging.103100","abstract":"Angiotensin-converting enzyme 2 (ACE2) is a member of the renin-angiotension system, however, the correlation between ACE2 and prognosis in UCEC (Uterine Corpus Endometrial Carcinoma) and KIRP (Kidney Renal Papillary Cell Carcinoma) is not clear. We analyzed the expression levels of ACE2 in the Oncomine and TIMER databases, the correlation between ACE2 and overall survival in the PrognoScan, GEPIA and Kaplan-Meier plotter databases. The correlation between ACE2 and immune infiltration level and the type markers of immune cells was investigated in TIMER database. A prognosis analysis based on the expression levels of ACE2 was further performed in related immune cells subgroup. The ACE2 promoter methylation profile was tested in the UALCAN database. In addition, we used GSE30589 and GSE52920 databases to elucidate the changes of ACE2 expression in vivo and in vitro after SARS-CoV infection. ACE2 was elevated in UCEC and KIRP, and high ACE2 had a favorable prognosis. The expression of ACE2 was positively correlated with the level of immune infiltration of macrophage in KIRP, B cell, CD4+T cell, neutrophil and dendritic cell immune infiltration levels in UCEC. ACE2 was significantly positively correlated with the type markers of B cells and neutrophils, macrophages in UCEC, while ACE2 in KIRP was positively correlated with the type markers of macrophages. High ACE2 expression level had a favorable prognosis in different enriched immune cells subgroups in UCEC and KIRP. And the promoter methylation levels of ACE2 in UCEC and KIRP were significantly reduced. What's more, we found that the expression of ACE2 decreased in vivo and in vitro after SARS-CoV infection. In conclusion, ACE2 expression increased significantly in UCEC and KIRP, elevated ACE2 was positively correlated with immune infiltration and prognosis. Moreover, tumor tissues may be more susceptible to SARS-CoV-2 infection in COVID-19 patients with UCEC and KIRP, which may worsen the prognosis.","type":"Research","database":"PubMed","created":"2020-05-05"},{"id":275,"name":"Noscapine, a possible drug candidate for attenuation of cytokine release associated with SARS\u2010CoV\u20102","author":"Soltan A. Ebrahimi","doi":"10.1002\/ddr.21676","abstract":"Successful treatment of viral infections has proven to be huge challenge for modern medicine with the most effective approach being prior vaccination. The problem with vaccination is the time it takes to develop an effective vaccine, validate its safety and manufacture it in large quantities. Facing Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), we simply do not have the time to develop the vaccine before thousands of people die. Therefore, any treatment which can decrease the severe symptoms due to lung damage may help attenuate mortality rates. Inactivation of ACE2 during virus fusion into the host cell may be one of the underlying reasons for intense immunological reaction seen in the lung tissue. This overreaction is probably mediated through the bradykinin receptor activation. Noscapine, a medication used for the treatment of cough, has been shown to inhibit bradykinin enhanced cough response in man. As it is already marketed in a number of countries as a cough medicine, even for children, a suitable formulation with all the required licenses is available that can be rapidly utilized in preliminary trials.","type":"Comment","database":"PubMed","created":"2020-05-05"},{"id":274,"name":"Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike Receptor-Binding Domain Bound with ACE2 COVID19 Target Proteins: A Virtual Drug Repurposing Study","author":"Serdar Durdagi, Busecan Aksoydan, Berna Dogan, Kader Sahin, Aida Shahraki, Necla Birg\u00fcl-\u0130yison","doi":"10.26434\/chemrxiv.12032712.v2","abstract":"In this virtual drug repurposing study, we used 7922 FDA approved drugs and compounds in clinical investigation from NPC database. Both apo and holo forms of SARS-CoV-2 Main Protease as well as Spike Protein\/ACE2 were used for virtual screening. Initially, docking was performed for these compounds at target binding sites. The compounds were then sorted according to their docking scores which represent binding energies. The first 100 compounds from each docking simulations were initially subjected to short (10 ns) MD simulations (in total 300 ligand-bound complexes), and average binding energies during MD simulations were calculated using the MM\/GBSA method. Then, the selected promising hit compounds based on average MM\/GBSA scores were used in long (100-ns and 500-ns) MD simulations. In total around 15 \u00b5s MD simulations were performed in this study. Both docking and MD simulations binding free energy calculations showed that holo form of the target protein is more appropriate choice for virtual drug screening studies. These numerical calculations have shown that the following 8 compounds can be considered as SARS-CoV-2 Main Protease inhibitors: Pimelautide, Rotigaptide, Telinavir, Ritonavir, Pinokalant, Terlakiren, Cefotiam and Cefpiramide. In addition, following 5 compounds were identified as potential SARS-CoV-2 ACE-2\/Spike protein domain inhibitors: Denopamine, Bometolol, Naminterol, Rotigaptide and Benzquercin. These compounds can be clinically tested and if the simulation results validated, they may be considered to be used as treatment for COVID-19.","type":"Research","database":"ChemRxiv","created":"2020-05-05"},{"id":273,"name":"Thermodynamics of the Interaction Between SARS-CoV-2 Spike Protein and Human ACE2 Receptor. Effects of Possible Ligands","author":"Cristina Garcia-Iriepa, Cecilia Hognon, Antonio Franc\u00e9s-Monerris, Isabel Iriepa, Tom Miclot, Giampaolo Barone, Antonio Monari, Marco Marazzi","doi":"10.26434\/chemrxiv.12186624.v1","abstract":"Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.","type":"Research","database":"ChemRxiv","created":"2020-05-05"},{"id":272,"name":"Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: a systematic review","author":"Veronique Michaud, Pamela Dow, Sweilem B Al Rihani, Malavika Deodhar, Meghan Arwood, Brian Cicali, Jacques Turgeon","doi":"10.1101\/2020.04.21.20066761","abstract":"Objective: To determine the relative risk of drug-induced Long QT Syndrome (LQTS) associated with SARS-CoV-2 (COVID-19) proposed repurposed drugs compared to well-known torsadogenic compounds. Setting: Computer calculations and simulations were performed using primary pharmacokinetic and pharmacodynamic data for each proposed drug. Seven different LQTS indices were calculated and compared. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Interventions: A thorough literature search was performed to gather information on the pharmacological properties of six drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir\/ritonavir, and remdesivir) repurposed to treat COVID-19. Researchers emphasized the affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval), and cause torsade de pointes (TdP). The risk of drug-induced LQTS for these drugs was quantified by comparing six indices that assess such risk. Primary and secondary outcome measures: Level of risk estimated for the six COVID-19 drugs being proposed compared to 23 torsadogenic drugs. Number of proarrhythmic adverse events identified for these drugs in the FAERS. Results: Estimators of LQTS risk levels indicated a very high or high risk for all COVID-19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug-induced LQTS for the six repurposed drugs and 23 torsadogenic compounds. Conclusion: The risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients prescribed these drugs.","type":"Review","database":"MedRxiv","created":"2020-05-04"},{"id":271,"name":"Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19.","author":"Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ","doi":"10.1111\/jth.14872","abstract":"The global pandemic of coronavirus disease 2019 (COVID-19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID-19 patients show elevated D-Dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI-1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID-19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre-existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients.","type":"Review","database":"PubMed","created":"2020-05-01"},{"id":270,"name":"Thoughts on What Chemists Can Contribute to Fighting SARS-CoV-2 - A Short Note on Hand Sanitizers, Drug Candidates and Outreach.","author":"Richert C, Opatz T, Senn-Bilfinger J","doi":"10.1002\/anie.202004721","abstract":"The SARS-CoV-2 outbreak causing the respiratory disease COVID-19 has left many chemists in academia without an obvious option to contribute to fighting the pandemic. Some of our recent experiences indicate that there are ways to overcome this dilemma. A three-pronged approach is proposed.","type":"Comment","database":"PubMed","created":"2020-05-01"},{"id":269,"name":"COVID-19 Drug Discovery Using Intensive Approaches.","author":"Asai A, Konno M, Ozaki M, Otsuka C, Vecchione A, Arai T, Kitagawa T, Ofusa K,  Yabumoto M, Hirotsu T, Taniguchi M, Eguchi H, Doki Y, Ishii H","doi":"10.3390\/ijms21082839","abstract":"Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.","type":"Review","database":"PubMed","created":"2020-05-01"},{"id":268,"name":"SARS-CoV-2 and COVID-19: What are our options? Where should we focus our attention on to find new drugs and strategies?","author":"Magro G","doi":"10.1016\/j.tmaid.2020.101685","abstract":"no abstract available.","type":"Comment","database":"PubMed","created":"2020-05-01"},{"id":267,"name":"SARS-CoV-2 Pandemic and The Need for Transplant-oriented Trials.","author":"Zaza G, Benedetti C, Fribourg M, Maggiore U, Azzi J, Riella LV, Cravedi P","doi":"10.1111\/tri.13626","abstract":"After the first reported case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Wuhan, China, in December 2019, the contagion has spread rapidly and has become a global pandemic. There are as of yet no published studies beyond the case series describing the incidence and clinical course of COVID-19 in transplant recipients, a population potentially at high risk due to the ongoing immunosuppression and higher risk of comorbidities. This pandemic has had a major impact in transplant physicians and healthcare workers as well and this crisis has meant reducing or even interrupting transplant program activity, with a subsequent impact on patient morbidity and mortality that is still hard to quantify.","type":"Comment","database":"PubMed","created":"2020-05-01"},{"id":266,"name":"Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives - A better synergy for future COVID-19 clinical trials.","author":"Shittu MO, Afolami OI","doi":"10.1186\/s40779-020-00240-0","abstract":"The recent outbreak of coronavirus disease 2019 (COVID-19), is now officially declared as a pandemic by the World Health Organization. As of now, there is no known effective pharmaceutical agent against the SARS-CoV-2 virus. However, several precautionary measures have been prescribed to prevent further spread of the virus, which include avoidance of social gatherings, proper handwashing, frequently disinfecting of used items and surfaces and so on. More recent studies have highlighted the possibility of treating patients infected with the novel SARS-CoV-2 virus with chloroquine and hydroxychloroquine, of which mechanism of action is not completely understood. We seek to draw the attention of the scientific community to the possibility of drastically reducing the effects of the virus on the affected patients and improving clinical trials outcome through the synergistic action of zinc and chloroquine in patients suffering from the coronavirus disease.","type":"Comment","database":"PubMed","created":"2020-05-01"},{"id":265,"name":"Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19.","author":"Huang J, Song W, Huang H, Sun Q","doi":"10.3390\/jcm9041131p","abstract":"An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCov) in vitro. In the United States, one case of COVID-19 was successfully treated with compassionate use of remdesivir in January of 2020. In addition, a clinically proven protease inhibitor, camostat mesylate, has been demonstrated to inhibit Calu-3 infection with SARS-CoV-2 and prevent SARS-2-spike protein (S protein)-mediated entry into primary human lung cells. Here, we systemically discuss the pharmacological therapeutics targeting RNA-dependent RNA polymerase (RdRp), proteinase and S protein for treatment of SARS-CoV-2 infection. This review should shed light on the fundamental rationale behind inhibition of SARS-CoV-2 enzymes RdRp as new therapeutic approaches for management of patients with COVID-19. In addition, we will discuss the viability and challenges in targeting RdRp and proteinase, and application of natural product quinoline and its analog chloroquine for treatment of coronavirus infection. Finally, determining the structural-functional relationships of the S protein of SARS-CoV-2 will provide new insights into inhibition of interactions between S protein and angiotensin-converting enzyme 2 (ACE2) and enable us to develop novel therapeutic approaches for novel coronavirus SARS-CoV-2.","type":"Review","database":"PubMed","created":"2020-05-01"},{"id":264,"name":"Discovery of Potential Multi-Target-Directed Ligands by Targeting Host-specific SARS-CoV-2 Structurally Conserved Main Protease<sup>$<\/sup>.","author":"Joshi RS, Jagdale SS, Bansode SB, Shankar SS, Tellis MB, Pandya VK, Chugh A, Giri AP, Kulkarni MJ","doi":"10.1080\/07391102.2020.1760137","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts are going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (MPro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of MPro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae MPro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of MPro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 MPro. In agreement with this, we performed screening of \u223c7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 MPro as the primary target. We identified several natural molecules like \u03b4-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 MPro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2020-05-01"},{"id":263,"name":"The anti-HIV Drug Nelfinavir Mesylate (Viracept) is a Potent Inhibitor of Cell Fusion Caused by the SARS-CoV-2 Spike (S) Glycoprotein Warranting further Evaluation as an Antiviral against COVID-19 infections","author":"Farhana Musarrat, Vladimir Chouljenko, Rafiq Nabi, Achyut Dahai, Seetharama Jois, Konstantin Kousoulas","doi":"10.1101\/2020.04.24.060376","abstract":"Coronaviruses belong to a group of enveloped, positive-single stranded RNA viruses that are known to cause severe respiratory distress in animals and humans. The current SARS coronavirus-2 (SARS CoV-2) pandemic has caused more than 2,000,000 infections globally and nearly 200,000 deaths. Coronaviruses enter susceptible cells via fusion of the viral envelope with the plasma membrane and\/or via fusion of the viral envelope with endosomal membranes after endocytosis of the virus into endosomes. Previous results with SARS and MERS CoV have shown that the Spike (S) glycoprotein is a major determinant of virus infectivity and immunogenicity. Herein, we show that expression of SARS CoV-2 S (S-n) glycoprotein after transient transfection of African green monkey kidney (Vero) cells caused extensive cell fusion in comparison to limited cell fusion caused by the SARS S (S-o) glycoprotein. S-n expression was detected intracellularly and on transfected Vero cell surfaces and caused the formation of very large multinucleated cells (syncytia) by 48 hours post transfection. These results are in agreement with published pathology observations of extensive syncytial formation in lung tissues of COVID-19 patients. This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies. A systematic screening of several drugs for ability to inhibit S-n and S-o cell fusion revealed that the FDA approved HIV-protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n and S-o-mediated cell fusion in a dose-dependent manner. Complete inhibition of cell fusion was observed at a 10 micromolar concentration. Computational modeling and in silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n and S-o-mediated membrane fusion. Also, it is possible that nelfinavir mesylate acts on cellular processes to inhibit S proteolytic processing. These results warrant further investigations of the potential of nelfinavir mesylate as an antiviral drug, especially at early times after SARS-CoV-2 symptoms appear.","type":"Research","database":"BioRxiv","created":"2020-04-29"},{"id":262,"name":"The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects","author":"Mizuki Yamamoto, Maki Kiso, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Masaki Imai, Makoto Takeda, Noriko Kinoshita, Norio Ohmagari, Jin Gohda, Kentaro Semba, Zene Matsuda, Yasushi Kawaguchi, Yoshihiro Kawaoka, Jun-ichiro Inou","doi":"10.1101\/2020.04.22.054981","abstract":"Although infection by SARS-CoV-2, the causative agent of COVID-19, is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked MERS-CoV S protein-initiated cell fusion by targeting TMPRSS2, and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on SARS-CoV-2 S protein, ACE2 and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an EC50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. These findings, together with accumulated clinical data regarding its safety, make nafamostat a likely candidate drug to treat COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-29"},{"id":261,"name":"Not One, But Five: Virtual Screening-Driven Drug Discovery of SARS-CoV2 Enzyme Inhibitors Targeting Viral Attachment, Replication and Post-Translational Infection Mechanisms","author":"Mark Tristan J. Quimque Kin Israel Notarte Rey Arturo T. Fernandez Mark Andrew O. Mendoza Rhenz Alfred D. Liman Justin Allen K. Lim Luis Agustin E. Pilapil Jehiel Karsten H. Ong Adriel M. Pastrana Allan Patrick Macabeo","doi":"10.26434\/chemrxiv.12170424.v1","abstract":"The novel coronavirus SARS-CoV2, the causative agent of the worldwide pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide have necessitated the need to discover substances that can be tapped for drug development. With the aid of bioinformatics and computational modelling, ninety seven secondary metabolites from fungi previously reported to exhibit antiviral properties were docked onto SARS-CoV2 enzymes involved in viral attachment, replication and post-translational mechanisms followed by in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, two fumiquinazoline alkaloids quinadoline B (19), scedapin C (15), and the polyketide isochaetochromin D1 (8) exhibited high binding affinities depending on the target protein. The compounds were active against the cysteine proteases, papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro) which are involved in post-translational modifications, RNA-directed RNA polymerase (RdRp) which is essential in viral replication, non-structural protein 15 (nsp15) which is involved in evasion of host immunity, and the spike protein which is responsible for binding to GRP78. Quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.","type":"Research","database":"ChemRxiv","created":"2020-04-24"},{"id":260,"name":"In Search for Effective and Safe Drugs Against SARS-CoV-2: Part I] Simulated Interactions Between Selected Nutraceuticals, ACE2 Enzyme and S Protein Simple Peptide Sequences","author":"M. Sabry Abdel-Mottaleb, Yousra Abdel-Mottaleb","doi":"10.26434\/chemrxiv.12155235.v1","abstract":"Coronavirus disease (COVID-19) remains a world pandemic with little treatment options. Nature has provided a plethora of compounds that may offer potential protection and\/or treatment choices. Earlier studies have shown a pivotal role of Angiotensin converting enzyme 2 (ACE2) in the pathogenesis of COVID-19. In this context, seven natural compounds were selected and their binding to specific peptide sequences of the coronavirus S-protein: ACE2 interface-drug binding adduct were calculated. Further to the natural drugs, we also similarly examined four well-known antiviral drugs. Moreover, the binding-interface of the isolated coronavirus S-protein and the isolated ACE2 receptor were also individually explored. The identified drug molecules positioned itself achieving geometries of minimum energy resulting in limiting viral recognition of host cells or to disturb host-virus interactions. The frontier orbitals (HOMO-LUMO) play crucial role in the binding interactions of the studied molecules. Most of the drugs act as electron sink whereas the S protein behaves as nucleophile. The results reported pave the way for the identification of small-drug molecule of natural origin with potentially tolerable side effects that can offer protection and\/or treatment against coronavirus S-protein COVID-19. Experimental validation is of urgent demand.","type":"Research","database":"ChemRxiv","created":"2020-04-24"},{"id":258,"name":"In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME","author":"Leif Peterson","doi":"10.26434\/chemrxiv.12155523.v1","abstract":"A in silico molecular dynamics (MD) docking investigation was conducted to identify drugs (ligands) which could potentially be of interest for repurposing. We sought ligands which formed the strongest binding potential energy with the x-ray crystallography-based active site of the SARS-CoV-2 protease C3Lpro. A total of 11,013 ligands were obtained from DrugBank. Because of the larger size of the active site of 3CLpro, we chose ligands whose molecular weight (MW) was greater than 400 (daltons) and less than 700, which resulted in 5,920 ligands. After correction of bonds and hydrogens, there were 4,634 ligands available for docking. Docking results indicate that the top 10 investigational and experimental drugs with binding energy (BE)\u2264-9 kcal\/mol were Lorecivivint, Tivantinib, Omipalisib, DrugBank B08450, SRT-2104, R-428, DrugBank B01897, Bictegravir, Ridinilazole, and Itacitinib, while the top 10 approved drugs with BE\u2264-8.2 were Olaparib, Etoposide, Ouabain, Indinavir, Idelalisib, Trametinib, Lumacaftor, Ergotamine, Canagliflozin, and Edoxaban. There were two antiviral drugs among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). The top 10 antivirals with BE\u2264-8.2 were Bictegravir, Tegobuvir, Filibuvir, Saquinavir, Fostemsavir, Indinavir, Temsavir, Pimodivir, Amenamevir, and Doravirine. Interestingly, the antiviral Remdesavir ranked low among the top 30 antivirals, since its BE was a low value of -7.5 kcal\/mol. In silico toxicology and ADME (absorption, distribution, metabolism, excretion) prediction indicates that only 20% (6\/30) of the top ligands were \u201cdrug-like,\u201d and none were \u201clead-like,\u201d since the lower bound of MW was 400. Another interesting finding was that the investigational natural supplement Diosmin (DrugBank ID B08995), used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE\u2264-6) with a strong BE=-8.8, and formed 8 hydrogen bonds with the active site for the putative best pose. Its energy-minimized 3D structure deeply penetrated and fully covered the width of the active site\u2019s pocket. Diosmin had a lower BE than 97% of the top 30 antiviral drugs and formed more hydrogen bonds with the active site than 93% of the top 30 antivirals. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be explored as a self-medicating natural alternative to prescribed synthetic drugs. Lastly, the green tea component epigallocatechin gallate (DrugBank ID B12116) also had a low BE=-8.3, and formed 2 hydrogen bonds with the active site, which was a BE that was better than 70% of the top 30 antivirals.","type":"Research","database":"ChemRxiv","created":"2020-04-24"},{"id":257,"name":"Bioactivity Profile Similarities to Expand the Repertoire of COVID-19 Drugs","author":"Miquel Duran-Frigola Martino Bertoni Roi Blanco Victor Martinez Eduardo Pauls Victor Alcalde Gemma Turon Nuria Villegas Adria Fernandez-Torras Carles Pons Lidia Mateo Oriol Guitart-Pla Pau Badia-i-Mompel Aleix Gimeno Nicolas Soler Isabelle Brun-Heath Hugo Zaragoza Patrick Aloy","doi":"10.26434\/chemrxiv.12178923.v1","abstract":"We present an online resource, based on small-molecule bioactivity signatures and natural language processing, to expand the portfolio of compounds with potential to treat COVID-19. By comparing the set of drugs reported to be potentially active against SARS-CoV-2 to a universe of 1M bioactive molecules, we identify compounds that display analogous chemical and functional features to the current COVID-19 candidates. Searches can be filtered by level of evidence and mechanism of action, and results can be restricted to drug molecules or include the much broader space of bioactive compounds. Moreover, we allow users to contribute COVID-19 drug candidates, which are automatically incorporated to the pipeline once per day. The computational platform, as well as the source code, is available at https:\/\/sbnb.irbbarcelona.org\/covid19.","type":"Other","database":"ChemRxiv","created":"2020-04-24"},{"id":256,"name":"Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients","author":"Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, Lijuan Xiong, Chunxia Guo, Jin Tian, Jinzhuo Luo, Jinghong Yao, Ran Pang, Hui Shen, Cheng Peng, Ting Liu, Qian Zhang, Jun Wu, Ling Xu, Sihong Lu, Baoju Wang, Zhihong Weng, Chunrong Han, Huabing Zhu, Ruxia Zhou, Helong Zhou, Xiliu Chen, Pian Ye, Bin Zhu, Lu Wang, Wenqing Zhou, Shengsong He, Yongwen He, Shenghua Jie, Ping Wei, Jianao Zhang, Yinping Lu, Weixian Wang, Li Zhang, Ling Li, Fen","doi":"10.1016\/j.ebiom.2020.102763","abstract":"Background\r\n\r\nThe dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear.\r\nMethods\r\n\r\nPeripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays.\r\nFindings\r\n\r\nOf the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts [0\u20226 (0\u20226-0\u20228)] but increases in neutrophil counts [4\u20227 (3\u20226-5\u20228)] than 27 mild cases [1.1 (0\u20228-1\u20224); 2\u20220 (1\u20225-2\u20229)]. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-\u03b3 levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-lymphocyte ratio (NLR) (AUC=0\u202293) and neutrophil-to-CD8+ T cell ratio (N8R) (AUC =0\u202294) were identified as powerful prognostic factors affecting the prognosis for severe COVID-19.\r\nInterpretation\r\n\r\nThe degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R and NLR may serve as a useful prognostic factor for early identification of severe COVID-19 cases.","type":"Research","database":"PubMed","created":"2020-04-24"},{"id":255,"name":"Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate target site concentrations derived from their established human pharmacokinetics","author":"Usman Arshad, Henry Pertinez, Helen Box, Lee Tatham, Rajith KR Rajoli, Paul Curley, Megan Neary, Joanne Sharp, Neill J Liptrott, Anthony Valentijn, Christopher David, Steve P Rannard, Paul O'Neill, Ghaith Aljayyoussi, Shaun Pennington, Stephen A Ward, David J Back, Saye H Khoo, Patrick G Bray, Giancarlo Biagini, Andrew Owen","doi":"10.1101\/2020.04.16.20068379","abstract":"Many papers are emerging that describe the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, no comprehensive evaluation of these molecules in the context of the achievable plasma pharmacokinetics after administration of approved doses and schedules to humans has been conducted. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax\/EC90 ratio). Only 14 of the analysed drugs achieved a Cmax\/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of these drugs demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax\/EC50 as a better indicator of potential human efficacy (lung Cmax\/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date is of variable quality and conducted under different conditions by different investigators. However, this analysis has prioritised candidates with the best chance for success in therapy or chemoprevention of Covid-19 based upon the currently available in vitro activity and human plasma pharmacokinetic data. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.","type":"Research","database":"MedRxiv","created":"2020-04-24"},{"id":254,"name":"Repositioned chloroquine and hydroxychloroquine as antiviral prophylaxis for COVID-19: A protocol for rapid systematic review of randomized controlled trials","author":"Raymond Chang, Wei-Zen Sun","doi":"10.1101\/2020.04.18.20071167","abstract":"Since the SARS-CoV-2 outbreak rapidly evolved into a pandemic, there is an urgent need for rapid development, identification and confirmation of efficacious antiviral prophylaxis. In this setting, the existing drugs chloroquine (CQ) and hydroxychloroquine (HCQ) which has suggestive evidence of efficacy against SARS-CoV-2 infection and COVID-19 disease has become prime candidates to be repositioned as therapeutic and preventative agents, and a growing number of clinical trials have been registered to study their preventative potential for at-risk populations using a range of dosing schemes and outcome measures. This rapid systematic review protocol aims to provide streamlined and timely synthesis on methodologies and results of randomized controlled trials assessing the efficacy of CQ and HCQ in hopes that this will constructively inform further research as well as public health policy.","type":"Review","database":"MedRxiv","created":"2020-04-24"},{"id":253,"name":"National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study","author":"Maxime Izoulet","doi":"10.1101\/2020.04.18.20063875","abstract":"COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group. This univariate analysis is of course only one additional piece of evidence in the debate regarding the efficiency of anti-malaria drugs, and it is also limited as the two groups certainly have other systemic differences in the way they responded to the pandemic, in the way they report death or in their population that better explain differences in dynamics (systematic differences that may also explain their choice to rely on anti-malaria drugs in the first place). Nevertheless, the difference in dynamics is so striking that we believe that the urgency context commands presenting the univariate analysis before delving into further analysis. In the end, this data might ultimately be either a piece of evidence in favor or anti-malaria drugs or a stepping stone in understanding further what other ecological aspects place a role in the dynamics of COVID-19 deaths.","type":"Other","database":"MedRxiv","created":"2020-04-24"},{"id":252,"name":"Old and new antirheumatic drugs for the treatment of COVID-19.","author":"Benucci M, Damiani A, Infantino M, Manfredi M, Quartuccio L","doi":"10.1016\/j.jbspin.2020.03.013","abstract":"\"The coronavirus disease 2019 (COVID-19) is spreading worldwide, with over 350,000 cases. In Italy, 69,176 cases with 6820 deaths were observed at March 24, so the World Health Association recently declared the pandemic feature of the infection [1]. SARS-CoV-2 belongs to the \u03b2-Coronaviridiae RNA virus family, which has long been recognized as responsible for infection in pets and respiratory diseases of varying severity in humans (i.e., severe acute respiratory syndrome coronavirus 2, abbreviated as SARS-CoV-2). Hence, the Coronavirus that infects humans can be divided into low and highly pathogenic [2]. SARS-CoV-2 is a new \u03b2-Coronavirus, probably a recombinant virus originating from bats. Recombination takes place within the Spike glycoprotein, which recognizes a cell surface receptor, thus allowing transmission between different species [3]. Most viruses enter cells via receptor-mediated endocytosis and in the case of COVID-19 it is assumed that Angiotensin 2 Conversion Receptor (ACE2) could be the receptor used to infect lung cells. ACE2 is highly expressed on pulmonary AT2 alveolar epithelial cells particularly prone to viral infection [4]. In a recent report from China [5], the clinical characteristics of COVID-19 can be reflected in at least three clinical models:\r\n\u2022    patients who are asymptomatic;\r\n\u2022    patients with mild to moderate disease;\r\n\u2022    patients with severe pneumonia who require admission to the intensive care unit (ICU).\r\n...\"","type":"Comment","database":"PubMed","created":"2020-04-24"},{"id":251,"name":"Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance","author":"Choudhary R, Sharma AK, Choudhary R","doi":"10.1016\/j.nmni.2020.100684","abstract":"Alarming situation has been caused due to the emergence of COVID-19 infection around the world. There is an urgency of developing a therapeutic strategy in order to control the spread of COVID-19. Towards that initiative, potential drugs like hydroxychloroquine, ivermectin and azithromycin have been tested by diverse group of researchers worldwide for their potential against novel coronavirus. The present report presents together the comprehensive knowledge derived from the major researches about the above drugs altogether in context of the current health emergency around the world. Hydroxychloroquine and ivermectin were known to act by creating the acidic environment and inhibiting the importin (IMP\u03b1\/\u03b21) mediated viral import. Azithromycin was found to act similar to the hydroxychloroquine as an acidotropic lipophilic weak base. All the three categories of drugs seemed to potentially act against novel coronavirus infection. However, their efficacies need to be studied in detail individually and in combination in-vivo in order to combat COVID-19 infection.","type":"Review","database":"PubMed","created":"2020-04-24"},{"id":250,"name":"Drug Development and Medicinal Chemistry Efforts Toward SARS-Coronavirus and Covid-19 Therapeutics.","author":"Ghosh AK, Brindisi M, Shahabi D, Chapman ME, Mesecar AD","doi":"10.1002\/cmdc.202000223","abstract":"The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell surface receptor, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA dependent RNA polymerase for RNA replication. There has been much ground work for drug discovery and development against these targets. Also, high throughput screening efforts led to identification of diverse lead structures, including product-derived molecules. The present review highlights past and present drug discovery and medicinal chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review will stimulate further research and will be a useful guide to the development of effective therapy against COVID-19 and other pathogenic coronaviruses.","type":"Review","database":"PubMed","created":"2020-04-24"},{"id":249,"name":"Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.","author":"Wenhao Dai, Bing Zhang, Haixia Su, Jian Li, Yao Zhao, Xiong Xie, Zhenming Jin, Fengjiang Liu, Chunpu Li, You Li, Fang Bai, Haofeng Wang, Xi Cheng, Xiaobo Cen, Shulei Hu, Xiuna Yang, Jiang Wang, Xiang Liu, Gengfu Xiao, Hualiang Jiang, Zihe Rao, Lei-Ke Zhang, Yechun Xu, Haitao Yang, Hong Liu","doi":"10.1126\/science.abb4489","abstract":"SARS-CoV-2 is the etiological agent responsible for the global COVID-19 outbreak. The main protease (M<sup>pro<\/sup>) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (<b>11a<\/b> and <b>11b<\/b>) targeting M<sup>pro<\/sup> Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The X-ray crystal structures of SARS-CoV-2 M<sup>pro<\/sup> in complex with <b>11a<\/b> or <b>11b<\/b>, both determined at 1.5 \u00c5 resolution, showed that the aldehyde groups of <b>11a<\/b> and <b>11b<\/b> are covalently bound to Cys145 of M<sup>pro<\/sup> Both compounds showed good PK properties in vivo, and <b>11a<\/b> also exhibited low toxicity, suggesting that these compounds are promising drug candidates.","type":"Research","database":"PubMed","created":"2020-04-24"},{"id":248,"name":"Computational Models Identify Several FDA Approved or Experimental Drugs as Putative Agents Against SARS-CoV-2","author":"Tesia Bobrowski Vinicius Alves Cleber C. Melo-Filho Daniel Korn Scott S. Auerbach Charles Schmitt Eugene Muratov Alexander Tropsha","doi":"10.26434\/chemrxiv.12153594.v1","abstract":null,"type":"Research","database":"ChemRxiv","created":"2020-04-23"},{"id":247,"name":"The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19","author":"Perricone C, Triggianese P, Bartoloni E, Cafaro G, Bonifacio AF, Bursi R, Perricone R, Gerli R","doi":"10.1016\/j.jaut.2020.102468","abstract":"The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed the world at a pandemic risk. Coronavirus-19 disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which causes pneumonia, requires intensive care unit hospitalization in about 10% of cases and can lead to a fatal outcome. Several efforts are currently made to find a treatment for COVID-19 patients. So far, several anti-viral and immunosuppressive or immunomodulating drugs have demonstrated some efficacy on COVID-19 both in vitro and in animal models as well as in cases series. In COVID-19 patients a pro-inflammatory status with high levels of interleukin (IL)-1B, IL-1 receptor (R)A and tumor necrosis factor (TNF)-\u03b1 has been demonstrated. Moreover, high levels of IL-6 and TNF-\u03b1 have been observed in patients requiring intensive-care-unit hospitalization. This provided rationale for the use of anti-rheumatic drugs as potential treatments for this severe viral infection. Other agents, such as hydroxychloroquine and chloroquine might have a direct anti-viral effect. The anti-viral aspect of immunosuppressants towards a variety of viruses has been known since long time and it is herein discussed in the view of searching for a potential treatment for SARS-CoV-2 infection.","type":"Comment","database":"PubMed","created":"2020-04-23"},{"id":246,"name":"D\u00e9j\u00e0 vu: stimulating open drug discovery for SARS-CoV-2","author":"Ekins S, Mottin M, Ramos PRPS, Sousa BKP, Neves BJ, Foil DH, Zorn KM, Braga RC, Coffee M, Southan C, Puhl AC, Andrade CH","doi":"10.1016\/j.drudis.2020.03.019","abstract":"In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the Americas and the current pandemic of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a strong sense of d\u00e9j\u00e0 vu because there are still no effective treatments. In the COVID-19 pandemic, despite being a new virus, there are already drugs suggested as active in in vitro assays that are being repurposed in clinical trials. Promising SARS-CoV-2 viral targets and computational approaches are described and discussed. Here, we propose, based on open antiviral drug discovery approaches for previous outbreaks, that there could still be gaps in our approach to drug discovery.","type":"Comment","database":"PubMed","created":"2020-04-23"},{"id":245,"name":"Perspectives for repurposing drugs for the coronavirus disease 2019","author":"Sarah S Cherian, Megha Agrawa, Atanu Basu, Priya Abraham, Raman R Gangakhedkar, Balram Bhargava","doi":"10.4103\/ijmr.IJMR_585_20","abstract":"The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach from earlier approved drugs could reduce the time and cost compared to de novo drug discovery. Direct virus-targeted antiviral agents target specific nucleic acid or proteins of the virus while host-based antivirals target either the host innate immune responses or the cellular machineries that are crucial for viral infection. Both the approaches necessarily interfere with viral pathogenesis. Here we summarize the present status of both virus-based and host-based drug repurposing perspectives for coronaviruses in general and the SARS-CoV-2 in particular.","type":"Review","database":"PubMed","created":"2020-04-23"},{"id":244,"name":"Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) - an update on the status","author":"Tarek Mohamed Abd El-Aziza, James D. Stockand","doi":"10.1016\/j.meegid.2020.104327","abstract":"Coronaviruses are a large group of viruses known to cause illnesses that vary between the common cold and more severe diseases to include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). A novel coronavirus was identified in December 2019 in Wuhan city, Hubei province, China. This virus represents a new strain that has not been previously identified in humans. The virus is now known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease is called coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared the novel coronavirus outbreak a global pandemic in March 2020. Despite rigorous global containment and quarantine efforts, the incidence of COVID-19 continues to rise, with more than 1,948,617 laboratory-confirmed cases and over 121,846 deaths worldwide. Currently, no specific medication is recommended to treat COVID-19 patients. However, governments and pharmaceutical companies are struggling to quickly find an effective drug to defeat the coronavirus. In the current review, we summarize the existing state of knowledge about COVID-19, available medications, and treatment options. Favilavir is an antiviral drug that is approved in Japan for common influenza treatment and is now approved to treat symptoms of COVID-19 in China. Moreover, Chloroquine and hydroxychloroquine, drugs used to treat malaria and arthritis, respectively, were recommended by the National Health Commission of the People's Republic of China for treatment of COVID-19. Presently, chloroquine and hydroxychloroquine are under investigation by the US Food and Drug Administration (FDA) as a treatment for COVID-19. The first COVID-19 vaccine is not expected to be ready for clinical trials before the end of the year.","type":"Review","database":"PubMed","created":"2020-04-23"},{"id":243,"name":"Structural Similarity of SARS-CoV2 Mpro and HCV NS3\/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics","author":"Khushboo Bafna, Robert M. Krug, Gaetano Montelione","doi":"10.26434\/chemrxiv.12153615.v1","abstract":"During the current COVID-19 pandemic more than 160,000 people have died worldwide as of mid-April 2020, and the global economy has been crippled. Effective control of the SARS-CoV2 virus that causes the COVID-19 pandemic requires both vaccines and antivirals. Antivirals are particularly crucial to treat infected people during the period of time that an effective vaccine is being developed and deployed. Because the development of specific antiviral drugs can take a considerable length of time, an important approach is to identify existing drugs already approved for use in humans which could be repurposed as COVID-19 therapeutics. Here we focus on antivirals directed against the SARS-CoV2 Mpro protease, which is required for virus replication. A structural similarity search showed that the Hepatitis C virus (HCV) NS3\/4A protease has a striking three-dimensional structural similarity to the SARS-CoV2 Mpro protease, particularly in the arrangement of key active site residues. We used virtual docking predictions to assess the hypothesis that existing drugs already approved for human use or clinical testing that are directed at the HCV NS3\/4A protease might fit well into the active-site cleft of the SARS-CoV2 protease (Mpro). AutoDock docking scores for 12 HCV protease inhibitors and 9 HIV-1 protease inhibitors were determined and compared to the docking scores for an alpha-ketoamide inhibitor of Mpro, which has recently been shown to inhibit SARS-CoV2 virus replication in cell culture. We identified eight HCV protease inhibitors that bound to the Mpro active site with higher docking scores than the alpha-ketoamide inhibitor, suggesting that these protease inhibitors may effectively bind to the Mpro active site. These results provide the rationale for us to test the identified HCV protease inhibitors as inhibitors of the SARS-CoV2 protease, and as inhibitors of SARS-CoV2 virus replication. Subsequently these repurposed drugs could be evaluated as COVID-19 therapeutics.","type":"Research","database":"ChemRxiv","created":"2020-04-23"},{"id":242,"name":"Repurposing FDA-Approved Drugs for COVID-19 Using a Data-Driven Approach","author":"Rodrigo R. R. Duarte, Dennis C. Copertino Jr., Luis P. I\u00f1iguez, Jez L. Marston, Douglas F. Nixon, Timothy R. Powell","doi":"10.26434\/chemrxiv.12148764.v1","abstract":"There have been more than 116,000 recorded deaths worldwide to-date caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19), and over 1.8 million individuals are currently infected. Although there are now hundreds of clinical trials for COVID-19, there are currently no effective licensed treatments, while the numbers of infected individuals continue to rise at an exponential rate in many parts of the world. Here, we used a data-driven approach utilizing connectivity mapping and the transcriptional signature of lung carcinoma cells infected with SARS-CoV-2, to search for drugs across the spectrum of medicine that have repurposing potential for treating COVID-19. We also performed chemoinformatic analyses to test whether the identified compounds were predicted to physically interact with the SARS-CoV-2 RNA-dependent RNA polymerase or main protease enzymes. Our study identified commonly prescribed FDA-approved molecules as important candidates for drug repositioning against COVID-19, including flupentixol, reserpine, fluoxetine, trifluoperazine, sunitinib, atorvastatin, raloxifene, butoconazole, and metformin. These drugs should not be taken for treating or preventing COVID-19 without a doctor\u2019s advice, as further research and clinical trials are now needed to elucidate their efficacy for this purpose.","type":"Research","database":"ChemRxiv","created":"2020-04-22"},{"id":241,"name":"Comparative Docking Analysis of Rational Drugs Against COVID-19 Main Protease","author":"LALIT SAMANT, Vyomesh Javle","doi":"10.26434\/chemrxiv.12136002.v1","abstract":"COVID-19, a new strain of coronavirus (CoV), was identified in Wuhan, China, in 2019. No specific therapies are available, and investigations regarding COVID-19 treatment are lacking. Crystallised COVID-19 main protease (Mpro), which is a potential drug target. The present study aimed to assess drugs found in literature as potential COVID-19 Mpro inhibitors, using a molecular docking study. Molecular docking was performed using Autodock 4.2, with the Lamarckian Genetic Algorithm, to analyse the probability of docking. The docking was cross-validated using Swiss Dock. COVID-19 Mpro was docked with several compounds, and docking was analysed by Biovia Discovery Studio 2020. Quinine and hydroxychloroquine were used as standards for comparison. The binding energies obtained from the docking of 6LU7, 2GTB with screened drugs viz., Quinine, Artesunate, Clotrimazol, Artemether, Quercetin, Mefloquine, ciprofloxacin, clindamycin, cipargamin, SJ-733 were in between -7.0 to -9.6 kcal\/mol. On consideration of similar binding energy obtained from Autodock vina and SWISSDock and interaction residue pattern specifically (GLU 166,CYS 145, CYS44 and MET 49 residue) for SJ-733 & JPC-3210 may represent potential treatment options, and appeared to have the best potential to act as COVID-19 Mpro inhibitors. However, further research is necessary to investigate their potential medicinal use against CoV.","type":"Research","database":"ChemRxiv","created":"2020-04-22"},{"id":240,"name":"Molecular docking and dynamics simulation of FDA approved drugs with the main protease from 2019 novel coronavirus","author":"Odhar HA, Ahjel SW, Albeer AAMA, Hashim AF, Rayshan AM, Humadi SS","doi":"10.6026\/97320630016236","abstract":"Design and development of an effective drug to combat the 2019 novel coronavirus remains a challenge. Therefore, it is of interest to study the binding features of 1615 FDA approved drugs with the recently known 2019-nCoV main protease structure having high sequence homology with that from SARS-CoV. We document the binding features of top 10 drugs with the target protein. We further report that Conivaptan and Azelastine are mainly involved in hydrophobic interactions with active site residues. Both drugs can maintain close proximity to the binding pocket of main protease during simulation. However, these data need further in vitro and in vivo evaluation to repurpose these two drugs against 2019-nCoV.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":239,"name":"Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes","author":"Elmezayen AD, Al-Obaidi A, \u015eahin AT, Yelek\u00e7i K","doi":"10.1080\/07391102.2020.1758791","abstract":"In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":238,"name":"Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study","author":"Wang J","doi":"10.1021\/acs.jcim.0c00179","abstract":"The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. The virus causing COVID-19 is SARS-Cov-2. Taking the advantage of a recently released crystal structure of SARS-Cov-2 main protease in complex with a covalently-bonded inhibitor, N3,1 I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS (Molecular Mechanics-Poisson Boltzmann Surface Area-Weighted Solvent-Accessible Surface Area).2-4 Several promising known drugs stand out as potential inhibitors of SARS-Cov-2 main protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal\/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal\/mol) is not nearly as low as that of the neutral form (-7.9 kcal\/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal\/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including SARS-Cov, SARS-Cov-2, MERS-Cov, and HCV. The findings of this study can facilitate rational drug design targeting the SARS-Cov-2 main protease.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":237,"name":"Novel 2019 Coronavirus Structure, Mechanism of Action, Antiviral drug promises and rule out against its treatment","author":"Boopathi S, Poma AB, Kolandaivel P","doi":"10.1080\/07391102.2020.1758788","abstract":"In the past two decades, the world has faced several infectious disease outbreaks. Ebola, Influenza A (H1N1), SARS, MERS, and Zika virus have had a massive global impact in terms of economic disruption, the strain on local and global public health. Most recently, the global outbreak of novel coronavirus 2019 (SARS-CoV-2) that causes COVID-19 is a newly discovered virus from the coronavirus family in Wuhan city, China, known to be a great threat to the public health systems. As of 15 April 2020, The Johns Hopkins University estimated that the COVID-19 affected more than two million people, resulting in a death toll above 130,000 around the world. Infected people in Europe and America correspond about 40% and 30% of the total reported cases respectively. At this moment only few Asian countries have controlled the disease, but a second wave of new infections is expected. Predicting inhibitor and target to the COVID-19 is an urgent need to protect human from the disease. Therefore, a protocol to identify anti-COVID-19 candidate based on computer-aided drug design is urgently needed. Thousands of compounds including approved drugs and drugs in the clinical trial are available in the literature. In practice, experimental techniques can measure the time and space average properties but they cannot be captured the structural variation of the COVID-19 during the interaction of inhibitor. Computer simulation is particularly suitable to complement experiments to elucidate conformational changes at the molecular level which are related to inhibition process of the COVID-19. Therefore, computational simulation is essential tool to elucidate the phenomenon. The structure-based virtual screening computational approach will be used to filter the best drugs from the literature, the investigate the structural variation of COVID-19 with the interaction of the best inhibitor is a fundamental step to design new drugs and vaccines which can combat the coronavirus. This mini-review will address novel coronavirus structure, mechanism of action, and trial test of antiviral drugs in the lab and patients with COVID-19.","type":"Review","database":"PubMed","created":"2020-04-22"},{"id":236,"name":"Coronavirus drugs: Using plasma from recovered patients as a treatment for COVID-19","author":"Alzoughool F, Alanagreh L","doi":"10.3233\/JRS-201017","abstract":"The ongoing COVID-19 pandemic has infected nearly 400,000 individuals with 17000 deaths since it was first identified in human populations in December 2019, in Wuhan, China. No antiviral therapies or vaccines are available for their treatment or prevention. Passive immunization PI through broadly neutralizing antibodies that bind to the specific antigens of SARS-CoV 2 might be a potential solution to address the immediate health threat of COVID-19 pandemic while vaccines are being developed. The PI approach in treating COVID-19 is discussed herein, including a summary of its historical applications to confront epidemics.","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":235,"name":"Combating Devastating COVID -19 by Drug Repurposing","author":"Pawar AY","doi":"10.1016\/j.ijantimicag.2020.105984","abstract":"no abstract available","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":234,"name":"Should Patients Receiving ACE Inhibitors or Angiotensin Receptor Blockers be Switched to Other Antihypertensive Drugs to Prevent or Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)?","author":"Trifir\u00f2 G, Crisafulli S, And\u00f2 G, Racagni G, Drago F; Italian Society of Pharmacology","doi":"10.1007\/s40264-020-00935-2","abstract":"no abstract available","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":233,"name":"Flooded by the torrent: the COVID-19 drug pipeline","author":"Mullard A","doi":"10.1016\/S0140-6736(20)30894-1","abstract":"no abstract available","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":232,"name":"Boosting the arsenal against COVID-19 through computational drug repurposing","author":"Ciliberto G, Cardone L","doi":"10.1016\/j.drudis.2020.04.005","abstract":"no abstract available","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":231,"name":"Pharmacologic treatment of transplant recipients infected with SARS-CoV-2: considerations regarding therapeutic drug monitoring and drug-drug interactions.","author":"Elens L, Langman LJ, Hesselink DA, Bergan S, Moes DJAR, Molinaro M, Venkataramanan R, Lemaitre F","doi":"10.1097\/FTD.0000000000000761","abstract":"BACKGROUND:\r\n\r\nCOVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-corona virus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs. It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals.\r\nMETHODS:\r\n\r\nThis article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of immunosuppressive drugs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature.\r\nRESULTS:\r\n\r\nManagement of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining immunosuppressive drug concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight.\r\nCONCLUSIONS:\r\n\r\nWith the present manuscript, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with immunosuppressive drugs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":230,"name":"Benefits and Risks of Chloroquine and Hydroxychloroquine in The Treatment of Viral Diseases: A Meta-Analysis of Placebo Randomized Controlled Trials","author":"Jing Wang, Li Yu, Kefeng Li","doi":"10.1101\/2020.04.13.20064295","abstract":"Background and Objective: Recently, in the scramble to find drugs to treat COVID-19, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have rapidly gained the public attention. In this study, we conducted a meta-analysis of randomized clinical trials (RCTs) to evaluate the efficacy and safety of CQ and HCQ in the treatment of viral diseases. Methods: We searched PubMed, EMBASE, Cochrane Central, Web of Science, Clinical Trials Registries, CNKI, Wanfang Data, CQVIP, and Preprint Servers through April 4, 2020, for randomized controlled trials (RCTs) that examined the efficacy and safety of CQ and HCQ against viral infection. We analyzed pooled data on the overall efficacy, the relative risks over the placebo, and the prevalence of adverse events. Trial sequential analysis (TSA) was also performed to evaluate the random errors in the meta-analysis. Potential moderators of drug-placebo efficacy differences were analyzed by meta-regression. Results: The analysis included 11 RCTs with 2613 adult patients. Both the plasma viral load (standard mean difference: 0.29, 95% CI: -1.19 - 1.76, P = 0.70) and the improvement of clinical symptoms (odds ratio: 2.36, 95% CI: 0.81 - 6.92, P = 0.11) were not different between the intervention and placebo arm. There was significant heterogeneity for the efficacy assessment, which was primarily explained by the age of patients and the sample size. Compared to the placebo, CQ and HCQ had increased risk of mild adverse events (risk ratio: 1.51, 95% CI: 1.35 - 1.70, P < 0.05, TSA adjusted 95% CI: 1.31 - 2.19), which were statistically significant in nervous, integumentary, and gastrointestinal systems. The most common adverse events were observed in the nervous system, with the pooled prevalence of 31.4% (95% CI: 10.5% - 56.7%). Conclusions: Insufficient data were available to support the antiviral efficacy of CQ and HCQ due to the high heterogeneity caused by the age of patients. Mild side effects are expected for the current antiviral dose regimens of CQ and HCQ. Treatment outcomes may be enhanced by better-selected patients based on age and well-controlled adverse events.","type":"Other","database":"MedRxiv","created":"2020-04-22"},{"id":229,"name":"Can prophylactic drugs keep fragile health systems running?","author":"Kupferschmidt K","doi":"10.1126\/science.368.6487.118","abstract":"no abstract available","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":228,"name":"Brief Summary of Potential SARS-CoV-2 Prophylactic and Treatment Drugs in the Emergency Department","author":"Brown C, Noble J, Coralic Z","doi":"10.5811\/westjem.2020.3.47328","abstract":"As of March 30th, 2020 there were 161,807 total cases and 2,953 total deaths of SARS-CoV-2 in the United States, with the number of cases expected to rise. Other than supportive care, there are no SARS-CoV-2 specific treatments available for patients discharged from the emergency department (ED) or those admitted to the hospital. In addition, there are no vaccines available to protect our at-risk healthcare workers. The National Institutes of Health is conducting a Phase 1 clinical trial to evaluate for a potential vaccine and the recipients have started to receive the investigational vaccine.2 We present a brief overview of the potential prophylactic and treatment agents under investigation, some which could be initiated in the ED if proven effective.","type":"Review","database":"PubMed","created":"2020-04-22"},{"id":227,"name":"Weak Induction of Interferon Expression by SARS-CoV-2 Supports Clinical Trials of Interferon Lambda to Treat Early COVID-19","author":"O'Brien TR, Thomas DL, Jackson SS, Prokunina-Olsson L, Donnelly RP, Hartmann R","doi":"10.1093\/cid\/ciaa453","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-04-22"},{"id":226,"name":"COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs","author":"Tufan A, Avano\u011flu G\u00fcler A, Matucci-Cerinic M","doi":"10.3906\/sag-2004-168","abstract":"In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines \u201ccytokine storm\u201d leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.","type":"Review","database":"PubMed","created":"2020-04-22"},{"id":225,"name":"Computational Drug Simulation: A Step to the Possible Cure of COVID-19","author":"Kumar Sharp, Shubhangi Dange","doi":"10.26434\/chemrxiv.12129129.v1","abstract":"World Health Organization declared COVID-19 as a pandemic on 11th March,2020. Without any exact cure or vaccine, this disease has certainly taken a toll of humanity. Computer-aided Drug Design (CADD) is the modern era simulator for aiding in finding cure before starting actual clinical trials in patients. We have not indulged into making a new drug but analysing the existing drugs as approved by FDA to find the possible cure options. Based on the above data from our study, we find that anti-inflammatory drugs like prednisone and anti-psychotic drugs can be used for targeting the spike glycoprotein of the SARS-CoV2 virus.","type":"Research","database":"ChemRxiv","created":"2020-04-22"},{"id":224,"name":"Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing","author":"Laura Riva, Shuofeng Yuan, Xin Yin, Laura Martin-Sancho, Naoko Matsunaga, Sebastian Burgstaller-Muehlbacher, Lars Pache, Paul P. De Jesus, Mitchell V. Hull, Max Chang, Jasper Fuk-Woo Chan, Jianli Cao, Vincent Kwok-Man Poon, Kristina Herbert, Tu-Trinh Nguyen, Yuan Pu, Courtney Nguyen, Andrey Rubanov, Luis Martinez-Sobrido, Wen-Chun Liu, Lisa Miorin, Kris M. White, Jeffrey R. Johnson, Christopher Benner, Ren Sun, Peter G. Schultz, Andrew Su, Adolfo Garcia-Sastre, Arnab K. Chatterjee, Kwok-Yung Yue","doi":"10.1038\/s41586-020-2577-1","abstract":"The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12\u201318 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose\u2013response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2,3,4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":223,"name":"Molecular Investigation of SARS\u2013CoV-2 Proteins and Their Interactions with Antiviral Drugs ","author":"Calligari P, Bobone S, Ricci G, Bocedi A","doi":"10.3390\/v12040445","abstract":"A new Coronavirus strain, named SARS-CoV-2, suddenly emerged in early December 2019. SARS-CoV-2 resulted in being dramatically infectious, with thousands of people infected. In this scenario, and without effective vaccines available, the importance of an immediate tool to support patients and against viral diffusion becomes evident. In this study, we exploit the molecular docking approach to analyze the affinity between different viral proteins and several inhibitors, originally developed for other viral infections. Our data show that, in some cases, a relevant binding can be detected. These findings support the hypothesis to develop new antiviral agents against COVID-19, on the basis of already established therapies.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":222,"name":"Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants","author":"Muhammad Tahir ul Qamar, Safar M. Alqahtani, Mubarak A. Alamri, Ling-Ling Chen","doi":"10.1016\/j.jpha.2020.03.009","abstract":"The recent outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in December 2019 raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals\/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":221,"name":"In Silico Identification of Widely Used and Well Tolerated Drugs That May Inhibit SARSCov- 2 3C-like Protease and Viral RNA-Dependent RNA Polymerase Activities, and May Have Potential to Be Directly Used in Clinical Trials","author":"Seref Gul, Onur Ozcan, Sinan Asar, Alper Okyar, Ibrahim Bar\u0131s, Ibrahim Halil Kavakli","doi":"10.1080\/07391102.2020.1802346","abstract":"We performed repurposing of FDA approved drugs against SARS-CoV-2 3 chymotrypsin like protease and RNA-dependent RNA polymerase. During the screening, 3948 drugs approved by the U.S. Food and Drug Administration (FDA) to target the active site of 3CLpro and nsp8 binding sites of RdRp and, in turn, disturb SARS-CoV-2 life cycle in host cell. As a result of molecular docking and molecular\r\ndynamics simulations, several drugs with high binding affinity to both SARS-Cov-2 3CLpro and RdRp targets were identified. While drugs such as tetracycline and its derivatives, dihydroergotamine, ergotamine, dutasteride, nelfinavir, paliperidone, and conivaptan were identified to bind SARS-Cov-2 3CLpro; tipranavir, nelfinavir, dihydroergotamine, conivaptan, dutasterid and eltrombopag were found to bind nsp8 binding site of RdRp. Notably, further analysis of the results showed that ergotamine,\r\ndihydroergotamine, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. Since these drugs are well tolerated, cost-effective and widely used, our study suggested that tetracycline and its derivatives, dutasteride, ergotamine, bromocriptine, tipranavir, conivaptan, paliperidone, eltrombopag drugs have the potential to be used alone or in combination as adjuvant for\r\nthe treatment of SARS-CoV-2 infected patients.","type":"Research","database":"PubMed","created":"2020-04-22"},{"id":220,"name":"Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach","author":"Mahmudul Hasan, Md Sorwer Alam Parvez, Kazi Faizul Azim, Abdus Shukur Imran, Topu Raihan, Airin Gulshan, Samuel Muhit, Rubaiat Nazneen Akhand, Md Bashir, Uddin Syed Sayeem Uddin Ahmed","doi":"10.26434\/chemrxiv.12118857.v1","abstract":"The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence\r\nof a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out\r\nthe effective drug candidates from the approved main protease protein (MPP) inhibitors and their\r\nderivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were\r\nemployed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against\r\nHIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide\r\nwere studied as control. The target drug surface hotspot was also investigated through the molecular\r\ndocking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness\r\nof the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal\/mol), and its\r\nanalog (CID 131982844)(-16.3 kcal\/mol) showed better binding affinity than the approved MPP inhibitor\r\ncompared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among\r\nthe screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,\r\nC145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot\r\nin the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),\r\nmay be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the\r\nmain protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir\r\nand its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved\r\nMPP inhibitors. ","type":"Research","database":"ChemRxiv","created":"2020-04-22"},{"id":219,"name":"Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods","author":"Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, Wang Q, Xu Y, Li M, Li X, Zheng M, Chen L, Li H","doi":"10.1016\/j.apsb.2020.02.008","abstract":"SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.","type":"Research","database":"PubMed","created":"2020-04-17"},{"id":218,"name":"Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing.","author":"Garcia-Cremades M, Solans BP, Hughes E, Ernest JP, Wallender E, Aweeka F, Luetkemeyer A, Savic RM","doi":"10.1002\/cpt.1856","abstract":"Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus Disease of 2019 (COVID-19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. The data sources included were 1) longitudinal clinical, pharmacokinetic, and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n=116), 2) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, 3) a population pharmacokinetic model of HCQ and 4) a model relating chloroquine pharmacokinetics to QTc prolongation. A mechanistic PK\/virologic\/QTc model for HCQ was developed and externally validated to predict SARS-CoV-2 rate of viral decline and QTc prolongation. SARS-CoV-2 viral decline was associated with HCQ pharmacokinetics (p<0.001). The extrapolated patient EC50 was 4.7 \u00b5M, comparable to the reported in vitro EC50 's. HCQ doses > 400 mg BID for \u22655 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS-CoV-2 infection, and shorten treatment courses, compared to lower dose (\u2264400 mg daily) regimens. However, HCQ doses >600 mg BID were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.","type":"Research","database":"PubMed","created":"2020-04-16"},{"id":217,"name":"Associations of clinical characteristics and antiviral drugs with viral RNA clearance in patients with COVID-19 in Guangzhou, China: a retrospective cohort study","author":"Xudan Chen, Yang Zhang, Baoyi Zhu, Jianwen Zeng, Wenxin Hong, Xi He, Jingfeng Chen, Haipeng Zheng, Shuang Qiu, Ying Deng, Juliana Chan, Jian Wang","doi":"10.1101\/2020.04.09.20058941","abstract":"Background: The novel coronavirus disease 2019 (COVID-19) characterized by respiratory symptoms has become a global pandemic although factors influencing viral RNA clearance remained unclear to inform optimal isolation period and treatment strategies. Methods: In this retrospective study, we included patients with confirmed COVID-19 admitted to Guangzhou Eighth People's Hospital from 20th January 2020 to 15th March 2020. The associations of clinical characteristics and treatment regimens on time to viral RNA clearance were analyzed. Results: We examined 284 consecutive COVID-19 cases, accounting for 82% of confirmed cases in Guangzhou during this period. At the time of reporting (20th March 2020), 276 (97.2%) had recovered and were discharged from hospital with a median hospital stay of 18 days (interquartile range [IQR]:13-24). Overall, 280 patients achieved viral RNA clearance with a median length of 12 days (IQR: 8-16) after onset of illness. Amongst them, 66.1% had viral RNA cleared within 14 days, and 89.3% within 21 days. Older age, severity of disease, time lag from illness onset to hospital admission, high body temperature, and corticosteroid use were associated with delayed clearance of viral RNA. None of the antiviral regimens (chloroquine, oseltamivir, arbidol, and lopinavir\/ritonavir) improved viral RNA clearance. The use of lopinavir\/ritonavir was associated with delayed clearance of viral RNA even after adjusting for confounders. Conclusion: In patients with COVID-19, isolation for a minimum of 21 days after onset of illness may be warranted, while the use of antiviral drugs does not enhance viral RNA clearance.","type":"Research","database":"MedRxiv","created":"2020-04-16"},{"id":216,"name":"Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial","author":"Wei Tang, Zhujun Cao, Mingfeng Han, Zhengyan Wang, Junwen Chen, Wenjin Sun, Yaojie Wu, Wei Xiao, Shengyong Liu, Erzhen Chen, Wei Chen, Xiongbiao Wang, Jiuyong Yang, Jun Lin, Qingxia Zhao, Youqin Yan, Zhibin Xie, Dan Li, Yaofeng Yang, Leshan Liu, Jieming Qu, Guang Ning, Guochao Shi, Qing Xie","doi":"10.1136\/bmj.m1849","abstract":"Objective To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19).\r\n\r\nDesign Multicentre, open label, randomised controlled trial.\r\n\r\nSetting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.\r\n\r\nParticipants 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone).\r\n\r\nInterventions Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).\r\n\r\nMain outcome measure Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.\r\n\r\nResults Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval \u201310.3% to 18.5%). In the safety population, adverse events were recorded in 7\/80 (9%) hydroxychloroquine non-recipients and in 21\/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7\/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.\r\n\r\nConclusions Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.\r\n\r\nTrial registration ChiCTR2000029868.","type":"Research","database":"PubMed","created":"2020-04-16"},{"id":215,"name":"The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells","author":"Hussin Rothan, Shannon Stone, Janhavi Natekar, Pratima Kumari, Komal Arora, Mukesh Kumar","doi":"10.1101\/2020.04.14.041228","abstract":"SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved gold drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 hours after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its anti-viral, anti-inflammatory and anti-ROS properties. Auranofin has a well-known toxicity profile and is considered safe for human use.","type":"Research","database":"BioRxiv","created":"2020-04-16"},{"id":214,"name":"TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-1 CoV-2 in human airway epithelial cells and provide promising drug targets ","author":"Dorothea Bestle, Miriam Ruth Heindl, Hannah Limburg, Thuy Van Lam van, Oliver Pilgram, Hong Moulton, David A. Stein, Kornelia Hardes, Markus Eickmann, Olga Dolnik, Cornelius Rohde, Stephan Becker, Hans-Dieter Klenk, Wolfgang Garten, Torsten Steinmetzer, Eva Bottcher-Friebertshauser","doi":"10.1101\/2020.04.15.042085","abstract":"In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines. In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1\/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2 site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-16"},{"id":213,"name":"Multidrug treatment with nelfinavir and cepharanthine against COVID-19","author":"Hirofumi Ohashi, Koichi Watashi, Wakana Saso, Kaho Shionoya, Shoya Iwanami, Takatsugu Hirokawa, Tsuyoshi Shirai, Shigehiko Kanaya, Yusuke Ito, Kwang Su Kim, Kazane Nishioka, Shuji Ando, Keisuke Ejima,","doi":"10.1101\/2020.04.14.039925","abstract":"Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir\/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-16"},{"id":212,"name":"No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial","author":"Matthieu Mahevas, Viet-Thi Tran, Mathilde Roumier, Amelie Chabrol, Romain Paule, Constance Guillaud, Sebastien Gallien, Raphael Lepeule, Tali-Anne Szwebel, Xavier Lescure, Frederic Schlemmer, Marie Ma","doi":"10.1101\/2020.04.10.20060699","abstract":"Background Treatments are urgently needed to prevent respiratory failure and deaths from coronavirus disease 2019 (COVID-19). Hydroxychloroquine (HCQ) has received worldwide attention because of positive results from small studies. Methods We used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen \u2265 2 L\/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg\/day. The composite primary endpoint was transfer to intensive care unit (ICU) within 7 days from inclusion and\/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47-1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation. Interpretation These results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.","type":"Research","database":"MedRxiv","created":"2020-04-15"},{"id":211,"name":"In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring","author":"Claudio Cavasotto, Juan Di Filippo","doi":"10.26434\/chemrxiv.12110199.v1","abstract":"In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, almost 1,5 million people have been infected, with more than 85,000 casualties. Today, no vaccine nor antiviral drug is available. While the development of a vaccine might take at least a year, and for a novel drug, even longer; finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a docking-based screening using a quantum mechanical scoring of a library built from approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like\r\nprotease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins.\r\nFollowing the anaylysis of our structure-based compound screening, we propose several structurally diverse compounds (either FDA-approved or in clinical trials) that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":210,"name":"Comparison of Clinically Approved Molecules on SARS-CoV-2 Drug Target Proteins: A Molecular Docking Study","author":"Hasan Cubuk, Mehmet Ozbil","doi":"10.26434\/chemrxiv.12090828.v1","abstract":"There are numerous drug design studies conducted all over the globe. Most of these studies target the receptor-binding domain of spike protein of SASR-CoV-2, which is known to bind human ACE2 receptor and SARS-CoV-2 main protease, vital for the virus\u2019 replication. However, there might be a third target, human furin protease, which cleaves the virus\u2019 S1-S2 domains taking active role in its entry into the host cell. In this study we docked five clinically used drug molecules, favipiravir, hydroxychloroquine, remdesivir, lopinavir, and ritonavir onto three target proteins, receptor binding domain of SARS-CoV-2 spike protein, SARS-CoV-2 main protease, and human furin protease. Computational results clearly showed that all ligands provided higher binding affinities towards furin protease, except hydroxychloroquine and ritonavir yielding the highest binding affinity. This proves that furin protease might be targeted for drug design studies and must be further explored in vitro and in vivo.","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":208,"name":"Drug Repurposing to Identify Therapeutics Against COVID 19 with SARS-Cov-2 Spike Glycoprotein and Main Protease as Targets: An in Silico Study","author":"arun kumar, Sharanya C.S, Abhithaj J, Sadasivan C","doi":"10.26434\/chemrxiv.12090408.v1","abstract":"The total cases of novel corona virus (SARS-CoV-2) infections is more than one million and total deaths recorded is more than fifty thousand. The research for developing vaccines and drugs against SARS-CoV-2 is going on in different parts of the world. Aim of the present study was to identify potential drug candidates against SARS-CoV-2 from existing drugs using in silico molecular modeling and docking. The targets for the present study was the spike protein and the main protease of SARS-CoV-2. The study was able to identify some drugs that can either bind to the spike protein receptor binding domain or the main protease of SARS-CoV-2. These include some of the antiviral drugs. These drugs might have the potential to inhibit the infection and viral replication.","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":207,"name":"Supercomputer-aided Drug Repositioning at Scale: Virtual Screening for SARS-CoV-2 Protease Inhibitor","author":"Sangjae Seo, Jung Woo Park, Dosik An, Junwon Yoon, Hyojung Paik, Soonwook Hwang","doi":"10.26434\/chemrxiv.12101457.v1","abstract":"Coronavirus diseases (COVID-19) outbreak has been labelled a pandemic. For the prioritization of treatments to cope with COVID-19, it is important to conduct rapid high-throughput screening of chemical compounds to repurposing the approved drugs, such as repositioning of chloroquine (Malaria drug) for COVID-19. In this study, exploiting supercomputer resource, we conducted high-throughput virtual screening for potential repositioning candidates of the protease inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using the three dimensional structure of main protease (Mpro) of SARS-CoV-2, we evaluated binding affinity between Mpro and drug candidates listed in SWEETLEAD library and ChEMBL database. Docking scores of 19,168 drug molecules at the active site of Mpro were calculated using Autodock Vina package. Among the calculated result, we selected 43 drug candidates and ran molecular dynamics (MD) simulation to further investigate protein-drug interaction. Among compounds that bind to the active site of SARS-CoV-2, we finally selected the 8 drugs showing the highest binding affinity; asunaprevir, atazanavir, dasabuvir, doravirine, fosamprenavir, ritonavir, voxilaprevir and amprenavir, which are the antiviral drugs of hepatitis C virus or human immunodeficiency virus. We expect that the present study provides comprehensive insights into the development of antiviral medication, especially for the treatment of COVID-19.","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":206,"name":"Potential SARS-CoV-2 protease Mpro inhibitors: repurposing FDA-approved drugs","author":"Valentina Kouznetsova, David Huang, Igor F. Tsigelny","doi":"10.1088\/1478-3975\/abcb66","abstract":"Using as a template the crystal structure of the SARS-CoV-2 main protease, we developed a pharmacophore model of functional centers of the protease inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of the SARS-CoV-2 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of the protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin\u2014the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.","type":"Research","database":"PubMed","created":"2020-04-14"},{"id":205,"name":"Computational Evaluation of the COVID-19 3c-like Protease Inhibition Mechanism, and Drug Repurposing Screening","author":"Hao Liu, Tao Jiang, Wenlang Liu, Zheng Zheng","doi":"10.26434\/chemrxiv.12090426.v1","abstract":"The rapid spread of the COVID-19 outbreak is now a global threat with over a million diagnosed cases and more than 70 thousand deaths. Specific treatments and effective drugs regarding such disease are in urgent need. To contribute to the drug discovery against COVID-19, we performed computational study to understand the inhibition mechanism of the COVID-19 3c-like protease, and search for possible drug candidates from approved or experimental drugs through drug repurposing screening against the DrugBank database. Two novel computational methods were applied in this study. We applied the \u201cConsecutive Histogram Monte Carlo\u201d (CHMC) sampling method for understanding the inhibition mechanism from studying the 2-D binding free energy landscape. We also applied the \u201cMovable Type\u201d (MT) free energy method for the lead compound screening by evaluating the binding free energies of the COVID-19 3c-like protease \u2013 inhibitor complexes. Lead compounds from the DrugBank database were first filtered using ligand similarity comparison to 19 published SARS 3c-like protease inhibitors. 70 selected compounds were then evaluated for protein-ligand binding affinities using the MT free energy method. 4 drug candidates with strong binding affinities and reasonable protein-ligand binding modes were selected from this study, i.e. Enalkiren (DB03395), Rupintrivir (DB05102), Saralasin (DB06763) and TRV-120027 (DB12199). ","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":204,"name":"Targeting SARS-CoV-2 Spike Protein of COVID-19 with Naturally Occurring Phytochemicals: An in Silco Study for Drug Development","author":"Preeti Pandey, Jitendra Subhash Rane, Aroni Chatterjee, Abhijeet Kumar, Rajni Khan, Amresh Prakash, Shashikant Ray","doi":"10.1080\/07391102.2020.1796811","abstract":"Spike glycoprotein, a class I fusion protein harboring the surface of SARS-CoV-2 (SARS-CoV-2S), plays a seminal role in the viral infection starting from recognition of the host cell surface receptor, attachment to the fusion of the viral envelope with the host cells. Spike glycoprotein engages host Angiotensin-converting enzyme 2 (ACE2) receptors for entry into host cells, where the receptor recognition and attachment of spike glycoprotein to the ACE2 receptors is a prerequisite step and key determinant of the host cell and tissue tropism. Binding of spike glycoprotein to the ACE2 receptor triggers a cascade of structural transitions, including transition from a metastable pre-fusion to a post-fusion form, thereby allowing membrane fusion and internalization of the virus. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been the active sources of different anti-microbial agents. We performed molecular docking studies using 10 potential naturally occurring compounds (flavonoids\/non-flavonoids) against the SARS-CoV-2 spike protein and compared their affinity with an FDA approved repurposed drug hydroxychloroquine (HCQ). Further, our molecular dynamics (MD) simulation and energy landscape studies with fisetin, quercetin, and kamferol revealed that these molecules bind with the hACE2-S complex with low binding free energy. The study provided an indication that these molecules might have the potential to perturb the binding of hACE2-S complex. In addition, ADME analysis also suggested that these molecules consist of drug-likeness property, which may be further explored as anti-SARS-CoV-2 agents.","type":"Research","database":"PubMed","created":"2020-04-14"},{"id":203,"name":"Drug Repurposing of Approved Drugs Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine and Ergotamine for Combating COVID19","author":"Vishal Mevada, Pravin Dudhagara, Himani Gandhi, Nilam Vaghamshi, Urvisha Beladiya, Rajesh Patel","doi":"10.26434\/chemrxiv.12115251.v1","abstract":"Pneumonia of unknown cause detected in Wuhan, China was first reported to the WHO Country Office in China on 31 December 2019. The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020. Currently, there is no Vaccine against COVID-19 pandemic and infection is spreading worldwide vary rapidly there is an exigent requirement of practicable drug treatment. Drug repurposing is one of the most promising approaches for that. Many reports are available with in silico drug repurposing but the majority of them engrossed on a single target. The present study aimed at screening the approved against Covid19 protein and extract the combination of operational comprehensively. A total of 1735 drug molecules against all COVID19 protein structures and sequential screening recognize the better potential of anti-HCV drugs over anti-HIV drugs. The study designated Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine Ergotamin as promising drug candidates for covid19 treatment. The computational analysis also reveled the better potential of proposed drugs over the currently used drug combination for COVID19 drugs. ","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":202,"name":"Interaction of Drug Candidates with Various SARS-CoV-2 Receptors: An in Silico Study to Combat COVID-19","author":"Romulo O. Barros, Fabio L. C. C. Junior, Wildrimak S. Pereira, Neiva M. N. Oliveira, Ricardo Ramos","doi":"10.1021\/acs.jproteome.0c00327","abstract":"The world is currently facing the COVID-19 pandemic caused by the SARS-CoV-2 virus. The pandemic is causing the death of people around the world, and public and social health measures to slow or prevent the spread of COVID-19 are being implemented with the involvement of all members of society. Research institutions are accelerating the discovery of vaccines and therapies for COVID-19. In this work, molecular docking was used to study (in silico) the interaction of 24 ligands, divided into four groups, with four SARS-CoV-2 receptors, Nsp9 replicase, main protease (Mpro), NSP15 endoribonuclease, and spike protein (S-protein) interacting with human ACE2. The results showed that the antimalarial drug Metaquine and anti-HIV antiretroviral Saquinavir interacted with all the studied receptors, indicating that they are potential candidates for multitarget drugs for COVID-19.","type":"Research","database":"PubMed","created":"2020-04-14"},{"id":201,"name":"Computational Guided Drug Repurposing for Targeting 2'-O-Ribose Methyltransferase of SARS-CoV-2","author":"Kedar Sharma, Sudhir Morla, Arun Goyal, Sachin Kumar","doi":"10.1016\/j.lfs.2020.118169","abstract":"Aims: The recent outbreak of pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led\r\nthe world towards a global health emergency. Currently, no proper medicine or effective treatment strategies are\r\navailable; therefore, repurposing of FDA approved drugs may play an important role in overcoming the situation.\r\nMaterials and methods: The SARS-CoV-2 genome encodes for 2-O-methyltransferase (2\u2032OMTase), which plays a\r\nkey role in methylation of viral RNA for evading host immune system. In the present study, the protein sequence\r\nof 2\u2032OMTase of SARS-CoV-2 was analyzed, and its structure was modeled by a comparative modeling approach\r\nand validated. The library of 3000 drugs was screened against the active site of 2\u2032OMTase followed by re-docking\r\nanalysis. The apo and ligand-bound 2\u2032OMTase were further validated and analyzed by using molecular dynamics\r\nsimulation.\r\nKey findings: The modeled structure displayed the conserved characteristic fold of class I MTase family. The\r\nquality assessment analysis by SAVES server reveals that the modeled structure follows protein folding rules and\r\nof excellent quality. The docking analysis displayed that the active site of 2\u2032OMTase accommodates an array of\r\ndrugs, which includes alkaloids, antivirals, cardiac glycosides, anticancer, steroids, and other drugs. The redocking and MD simulation analysis of the best 5 FDA approved drugs reveals that these drugs form a stable\r\nconformation with the 2\u2032OMTase.\r\nSignificance: The results suggested that these drugs may be used as potential inhibitors for 2\u2032OMTase for combating the SARS-CoV-2 infection.","type":"Research","database":"PubMed","created":"2020-04-14"},{"id":200,"name":"Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase I","author":"Mayla Borba, Fernando de Almeida Val, Vanderson Sousa Sampaio, Marcia Araujo Alexandre, Gisely Cardoso Melo, Marcelo Brito, Maria Mourao, Jose Diego Brito Sousa, djane Baia-da-Silva, Marcus Vinitius F","doi":"10.1101\/2020.04.07.20056424","abstract":"Summary Background There is no specific antiviral therapy recommended for the disease caused by SARS-CoV-2 (COVID-19). Recent publications have drawn attention to the possible benefit of chloroquine (CQ). Our study aimed to comprehensively evaluate the safety and efficacy of two different CQ dosages in patients with established severe COVID-19. Methods We performed a parallel, double-blinded, randomized, phase IIb clinical trial, aiming to assess safety and efficacy of two different CQ dosages as adjunctive therapy of hospitalized patients with SARS in Manaus, Brazilian Amazon. Eligible participants were allocated to receive orally or via nasogastric tube high dose CQ (600mg CQ twice daily for 10 days or total dose 12g); or low dose CQ (450mg for 5 days, twice daily only on the first day, or total dose 2.7g). In addition, all patients received ceftriaxone and azithromycin. This study was registered with ClinicalTrials.gov, number NCT04323527. Findings Out of a pre-defined 440 patients sample size, 81 patients were enrolled. The high dose CQ arm presented more QTc>500ms (25%), and a trend toward higher lethality (17%) than the lower dosage. Fatality rate was 13.5% (95%CI=6.9-23.0%), overlapping with the CI of historical data from similar patients not using CQ (95%CI=14.5-19.2%). In 14 patients with paired samples, respiratory secretion at day 4 was negative in only one patient. Interpretation Preliminary findings suggest that the higher CQ dosage (10-day regimen) should not be recommended for COVID-19 treatment because of its potential safety hazards. Such results forced us to prematurely halt patient recruitment to this arm. Given the enormous global push for the use of CQ for COVID-19, results such as the ones found in this trial can provide robust evidence for updated COVID-19 patient management recommendations.","type":"Research","database":"MedRxiv","created":"2020-04-14"},{"id":199,"name":"Classical drug digitoxin inhibits influenza cytokine storm, with implications for COVID-19 therapy.","author":"Harvey B Pollard, Bette S. Pollard, John R. Pollard","doi":"10.1101\/2020.04.09.034983","abstract":"Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing a hyper-proinflammatory response by immune cells and cytokines in the host airway. Here we show that the cardiac glycoside digitoxin suppresses this response induced by influenza virus strain A\/Wuhan\/H3N2\/359\/95 in the cotton rat lung. The cytokines TNFa, GRO\/KC, MIP2, MCP1, TGFb, and IFNg. are significantly reduced. Since the hyper-proinflammatory overproduction of cytokines is a host response, we suggest that digitoxin may have therapeutic potential for not only influenza and but also for coronovirus infections.","type":"Research","database":"BioRxiv","created":"2020-04-14"},{"id":198,"name":"Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug","author":"Zhenming Jin, Yao Zhao, Yuan Sun, Bing Zhang, Haofeng Wang, Yan Wu, Yan Zhu, Chen Zhu, Tianyu Hu, Xiaoyu Du, Yinkai Duan, Jing Yu, Xiaobao Yang, Xiuna Yang, Xiang Liu, Luke W. Guddat, Gengfu Xiao, Lei","doi":"10.1101\/2020.04.09.033233","abstract":"COVID-19 virus is the cause of a debilitating and life-threatening infectious pulmonary disease that is now responsible for a global pandemic. Currently, there are no specific drugs or vaccines to contain this virus. The main protease (Mpro) of COVID-19 virus is a key enzyme, which plays an essential role in viral replication and transcription, making it an ideal drug target. An FDA-approved antineoplastic drug, carmofur, has been identified as an inhibitor that targets COVID-19 virus Mpro. However, its inhibitory mechanism is unknown. Here, we report the 1.6-\u00c5 crystal structure of COVID-19 virus Mpro in complex with carmofur. The crystal structure shows that carmofur contains an electrophilic carbonyl reactive group, which covalently binds to C145, a member of the catalytic dyad. As a result, its fatty acid tail occupies the hydrophobic S2 subsite of Mpro whilst its 5-fluorouracil head is cleaved as product of the new covalent bond that has formed. Carmofur is active in a cell based antiviral assay with an EC50 of 24.87 \u03bcM. It is therefore a promising lead compound for the development of new antivirals to target COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-14"},{"id":197,"name":"Reversal of Infected Host Gene Expression Identifies Repurposed Drug Candidates for COVID-19","author":"Jing Xing, Rama Shankar, Aleksandra Drelich, Shreya Paithankar, Eugene Chekalin, Thomas Dexheimer, Surender Rajasekaran, Chien-Te Kent Tseng, Bin Chen","doi":"10.1101\/2020.04.07.030734","abstract":"Repurposing existing drugs is a timely option to cope with COVID-19. We predicted therapeutic candidates that could reverse the gene expression of coronavirus-infected host cells. Thirteen expression signatures computed from various experimental conditions and preclinical models could be reversed by those compounds known to be effective against SARS- or MERS-CoV, as well as the drug candidates recently shown to be effective against SARS-CoV-2. We selected ten novel candidates to further evaluate their in vitro efficacy against SARS-CoV-2 infection. Four compounds bortezomib, dactolisib, alvocidib and methotrexate inhibited the formation of virus infection-induced cytopathic effect in Vero E6 cells at 1 uM, yet such a concentration seems toxic to the cells as well. While the evaluation in other permissive cells and the prediction of toxicity are needed to optimize and minimize their antiviral activity and cytotoxicity, respectively, this computational approach has the potential to rapidly and rationally identify drug candidates against COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-14"},{"id":196,"name":"In Silico Discovery of Candidate Drugs against Covid-19","author":"Cava C, Bertoli G, Castiglioni I","doi":"10.3390\/v12040404","abstract":"Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.","type":"Research","database":"PubMed","created":"2020-04-14"},{"id":195,"name":"Computational Search for Potential COVID-19 Drugs from FDA-Approved Drugs and Small Molecules of Natural Origin Identifies Several Anti-Virals and Plant Products","author":"Abhishek Sharma, Vikas Tiwari, Ramanathan Sowdhamini","doi":"10.26434\/chemrxiv.12091356.v1","abstract":"The world is facing COVID-19 pandemic at the present time, for which mild symptoms include fever and dry cough. In severe cases it could lead to pneumonia and ultimately death in some instances. The pathogen, SARS-CoV-2, is one of the human coronaviruses which was identified to infect humans first in December 2019. We have interrogated the capacity to repurpose around 2300 FDA-approved drugs and more than 300,000 small molecules of natural origin towards drug identification through virtual screening and molecular dynamics. Interestingly, we observed simple molecules like lactose, previously known anti-virals and few secondary metabolites of plants as promising hits.","type":"Research","database":"ChemRxiv","created":"2020-04-14"},{"id":194,"name":"Targeting SARS-CoV-2: A Systematic Drug Repurposing Approach to Identify Promising Inhibitors Against 3C-like Proteinase and 2'-O-RiboseMethyltransferase.","author":"Khan RJ, Jha RK, Amera G, Jain M, Singh E, Pathak A, Singh RP, Muthukumaran J, Singh AK","doi":"10.1080\/07391102.2020.1753577","abstract":"The recent pandemic associated with SARS-CoV-2, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify promising inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (\u0394G), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (\u0394G= -9.8\u2009kcal\/mol) &Raltegravir (\u0394G= -7.8\u2009kcal\/mol) for 3CLpro and Dolutegravir (\u0394G= -9.4\u2009kcal\/mol) and Bictegravir (\u0394G= -8.4\u2009kcal\/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against SARS-CoV-2.","type":"Research","database":"PubMed","created":"2020-04-11"},{"id":193,"name":"Structure of Mpro from COVID-19 virus and discovery of its inhibitors","author":"Zhenming Jin, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, Xiaofeng Li, Leike Zhang, Chao Peng, Yinkai Duan, Jing Yu, Lin Wang, Kailin Yang, Fengjiang Liu, Rendi Jiang, Xing","doi":"10.1038\/s41586-020-2223-y","abstract":"A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1\u20134. Currently there are no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these compounds inhibited Mpro with IC50 values ranging from 0.67 to 21.4 \u03bcM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.","type":"Research","database":"PubMed","created":"2020-04-10"},{"id":192,"name":"Identification of Potential Inhibitors of SARS-CoV-2 Main Protease via a Rapid In-Silico Drug Repurposing Approach","author":"Cesar Mendoza-Martinez, Alejandro Rodriguez-Lezama","doi":"10.26434\/chemrxiv.12085083.v1","abstract":"An in-silico drug repurposing study was carried out to search for potential COVID-19 antiviral agents. A dataset of 1615 FDA-approved drugs was docked in the active site of SARS CoV-2 Main protease. A subset of the top scoring hit compounds was subjected to follow-up molecular dynamics simulations to further characterise the predicted binding modes. The main findings are that the drugs Aliskiren, Capreomycin, Isovuconazonium, emerge as novel potential inhibitors. We also observed that Ceftolozane, Cobicistat, Carfilzomib and Saquinavir are well-ranked by our protocol, in agreement with other recent in silico drug repurposing studies, however MD simulations shows only potential for the three first, as Saquinavir exhibited an unstable binding mode. As many HIV-protease inhibitors has been reported as active and not active, Atazanavir and Lopinavir were included in the data set in order to rationalize the findings. In addition, our protocol ranked favourably Dronedarone suggesting that this recently reported SARS-CoV-2 inhibitor targets SARS-CoV-2 Main protease.","type":"Research","database":"ChemRxiv","created":"2020-04-09"},{"id":191,"name":"The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15","author":"Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi","doi":"10.1101\/2020.03.11.987016","abstract":"Steroid compounds, which are expected to have dual functions in blocking host inflammation and MERS-CoV replication, were screened from a chemical library. Within this library, ciclesonide, an inhaled corticosteroid, suppressed human coronavirus replication in cultured cells, but did not suppress replication of respiratory syncytial virus or influenza virus. The effective concentration of ciclesonide to block SARS-CoV-2 (the cause of COVID-19) replication (EC90) was 6.3 M. After the eleventh consecutive MERS-CoV passage in the presence of ciclesonide, a resistant mutation was generated, which resulted in an amino acid substitution (A25V) in nonstructural protein (NSP) 15, as identified using reverse genetics. A recombinant virus with the mutation was also resistant to ciclesonide suppression of viral replication. These observations suggest that the effect of ciclesonide was specific to coronavirus, suggesting this is a candidate drug for treatment of patients suffering MERS or COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-07"},{"id":190,"name":"SARS-CoV-2 invades host cells via a novel route: CD147-spike protein","author":"Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, Bin Wang, Xiu-Xuan Sun, Chun-Fu Wang, Xu Yang, Peng Lin, Yong-Qiang Deng, Ding Wei","doi":"10.1101\/2020.03.14.988345","abstract":"Currently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world; nevertheless, so far there exist no specific antiviral drugs for treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 g\/mL and IC50 of 15.16 g\/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85x10-7M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.","type":"Research","database":"BioRxiv","created":"2020-04-07"},{"id":189,"name":"Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase","author":"Jingyue Ju, Xiaoxu Li, Shiv Kumar, Steffen Jockusch, Minchen Chien, Chuanjuan Tao, Irina Morozova, Sergey Kalachikov, Robert N. Kirchdoerfer, James J. Russo","doi":"10.1002\/prp2.674","abstract":"SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV\/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3-fluoro-3-deoxythymidine triphosphate, 3-azido-3-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.","type":"Research","database":"BioRxiv","created":"2020-04-07"},{"id":187,"name":"PolypharmDB, a Deep Learning-Based Resource, Quickly Identifies Repurposed Drug Candidates for COVID-19","author":"Dar'ya S. Redka Stephen S. MacKinnon Melissa Landon Andreas Windemuth Naheed Kurji Vijay Shahani","doi":"10.26434\/chemrxiv.12071271.v1","abstract":"There is an immediate need to discover treatments for COVID-19, the pandemic caused by the SARS-CoV-2 virus. Standard small molecule drug discovery workflows that start with library screens are an impractical path forward given the timelines to discover, develop, and test clinically. To accelerate the time to patient testing, here we explored the therapeutic potential of small molecule drugs that have been tested to some degree in a clinical environment, including approved medications, as possible therapeutic interventions for COVID-19. Motivating our process is a concept termed polypharmacology, i.e. off-target interactions that may hold therapeutic potential. In this work, we used Ligand Design, our deep learning drug design platform, to interrogate the polypharmacological profiles of an internal collection of small molecule drugs with federal approval or going through clinical trials, with the goal of identifying molecules predicted to modulate targets relevant for COVID-19 treatment. Resulting from our efforts is PolypharmDB, a resource of drugs and their predicted binding of protein targets across the human proteome. Mining PolypharmDB yielded molecules predicted to interact with human and viral drug targets for COVID-19, including host proteins linked to viral entry and proliferation and key viral proteins associated with the virus life-cycle. Further, we assembled a collection of prioritized approved drugs for two specific host-targets, TMPRSS2 and cathepsin B, whose joint inhibition was recently shown to block SARS-CoV-2 virus entry into host cells. Overall, we demonstrate that our approach facilitates rapid response, identifying 30 prioritized candidates for testing for their possible use as anti-COVID drugs. Using the PolypharmDB resource, it is possible to identify repurposed drug candidates for newly discovered targets within a single work day. We are making a complete list of the molecules we identified available at no cost to partners with the ability to test them for efficacy, in vitro and\/or clinically.","type":"Research","database":"ChemRxiv","created":"2020-04-05"},{"id":185,"name":"3CL<sup>pro<\/sup> inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials.","author":"Sisay M","doi":"10.1016\/j.phrs.2020.104779","abstract":"No abstract available","type":"Other","database":"PubMed","created":"2020-04-01"},{"id":184,"name":"Repurposing antimalarials and other drugs for COVID-19.","author":"Schlagenhauf P, Grobusch MP, Maier JD, Gautret P","doi":"10.1016\/j.tmaid.2020.101658","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-04-01"},{"id":183,"name":"Conformations and Three-Dimensional Structures of Selected SARS-CoV-2 Drug Candidates","author":"Karl Kirschner, Wolfgang Heiden","doi":"10.26434\/chemrxiv.12058959.v1","abstract":"Quantum mechanical theories are used to search and optimized the conformations of proposed small molecule candidates for treatment of SARS-CoV-2. These candidate compounds are taken from what is reported in the news and in other pre-peer-reviewed literature (e.g. ChemRxiv, bioRxiv). The goal herein is to provided predicted structures and relative conformational stabilities for selected drug and ligand candidates, in the hopes that other research groups can make use of them for developing a treatment.","type":"Research","database":"ChemRxiv","created":"2020-04-02"},{"id":182,"name":"Harmonizing heterogeneous endpoints in COVID-19 trials without loss of information - an essential step to facilitate decision making","author":"Maja von Cube, Marlon Grodd, Martin Wolkewitz, Derek Hazard, Jerome Lambert","doi":"10.1101\/2020.03.31.20049007","abstract":"Background: Many trials are now underway to inform decision-makers on potential effects of treatments for COVID-19. To provide sufficient information for all involved decision-makers (clinicians, public health authorities, drug regulatory agencies) a multiplicity of endpoints must be considered. It is a challenge to generate detailed high quality evidence from data while ensuring fast availability and evaluation of the results. Methods: We reviewed all interventional COVID-19 trials on Remdesivir, Lopinavir\/ritonavir and Hydroxychloroquine registered in the National Library of Medicine (NLM) at the National Institutes of Health (NIH) and summarized the endpoints used to assess treatment effects. We propose a multistate model that harmonizes heterogeneous endpoints and differing lengths of follow-up within and between trials. Results: There are currently, March 27, 2020, 23 registered interventional trials investigating the potential benefits of Remdesivir, Lopinavir\/ritonavir and Hydroxychloroquine. The endpoints are highly heterogeneous. Follow-up for the primary endpoints ranges from four to 168 days. A detailed precisely defined endpoint has been proposed by the global network REMAP-CAP, which is specialized on community-acquired pneumonia. Their seven-category endpoint accounts for major clinical events informative for all decision-makers. Moreover, the Core Outcome Measures in Effectiveness Trials (COMET) Initiative is currently working on a core outcome set. We propose a multistate model that accommodates analysis of these recommended endpoints. The model allows for a detailed investigation of treatment effects for various endpoints over the course of time thereby harmonizing differing endpoints and lengths of follow-up. Conclusion: Multistate model analysis is a powerful tool to study clinically heterogeneous endpoints (mortality, discharge) as well as endpoints influencing hospital capacities (duration of hospitalization and ventilation) simultaneously over time. Our proposed model extracts all information available in the data and is - by harmonizing endpoints within and between trials - a step towards faster decision making. All ongoing clinical trials, especially those with severe cases, should accommodate primary analysis with a stacked probability plot of the major events mechanical ventilation, discharge alive and death.","type":"Research","database":"MedRxiv","created":"2020-04-02"},{"id":181,"name":"SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles","author":"Denisa Bojkova, Jake E. McGreig, Katie-May McLaughlin, Stuart G. Masterson, Marek Widera, Verena Kr\u00e4hling, Sandra Ciesek, Mark N. Wass, Martin Michaelis, Jindrich Cinatl jr.","doi":"10.1101\/2020.04.03.024257","abstract":"SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.","type":"Research","database":"BioRxiv","created":"2020-04-04"},{"id":179,"name":"Drugs and the renin-angiotensin system in covid-19.","author":"Aronson JK, Ferner RE","doi":"10.1136\/bmj.m1313","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-04-01"},{"id":178,"name":"Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infectionwith reference to use of therapeutic and other drugs used in Co-morbid diseases (Hypertension, diabetes etc).","author":"Ritesh Gupta, Anoop Misra","doi":"10.1016\/j.dsx.2020.03.012","abstract":"BACKGROUND AND AIMS:\r\n\r\nMultiple issues in management of COVID have emerged, but confusion persists regarding rational interpretation. Aim of this brief review is to review these issues based on current literature.\r\nMETHODS:\r\n\r\nThis is a narrative review with Pubmed and Google Scholar search till 23 March 2020. Search terms were, COVID-19, treatment of coronavirus, COVID 19 and following terms; chloroquine, hydroxychloroquine, ibuprofen, ACE-inhibitors or angiotensin receptor blockers, cardiovascular disease, diarrhoea, liver, testis and gastrointestinal disease.\r\nRESULTS:\r\n\r\nWe discuss evidence regarding role of chloroquine and hydroxychloroquine in treatment and prophylaxis, use of inhibitors of the renin angiotensin system, safety of ibuprofen, unusual clinical features like gastrointestinal symptoms and interpretation of tests for cardiac enzymes and biomarkers.\r\nCONCLUSIONS:\r\n\r\nWhile our conclusions on management of COVID-19 patients with co-morbidities are based on current evidence, however, data is limited and there is immediate need for fast track research.","type":"Review","database":"PubMed","created":"2020-03-24"},{"id":177,"name":"Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection.","author":"Yin\u2010Xiao Du, Xiao\u2010Ping Chen","doi":"10.1002\/cpt.1844","abstract":"An outbreak of 2019-nCoV infection in China has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the recommended antiviral drugs such as interferon-\u0251, lopinavir\/ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug-drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.","type":"Research","database":"PubMed","created":"2020-04-03"},{"id":175,"name":"Immunosuppression drug-related and clinical manifestation of Coronavirus disease 2019: a therapeutical hypothesis.","author":"Romanelli Antonio, Mascolo Silvia","doi":"10.1111\/ajt.15905","abstract":"We read with interest the article of Guillen et al. <sup>1<\/sup> . Here, the authors described the management of a kidney transplanted patient infected by SARS-CoV-2 that causes novel Coronavirus disease 2019 (COVID-19). The authors stated that immunosuppressed patients might present with atypical clinical manifestation (fever, diarrhea, fatigue) without respiratory symptoms. Also Li and colleagues <sup>2<\/sup> reported SARS-CoV-2 infection in two solid organ transplanted patients. The two heart transplanted patients presented with variable severity of COVID-19 (one mild and another with more severe manifestations requiring a prolonged hospitalization), however, both survived the event.","type":"Comment","database":"PubMed","created":"2020-04-02"},{"id":174,"name":"FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro","author":"Stuart Weston, Rob Haupt, James Logue, Krystal Matthews, Matthew B. Frieman","doi":"10.1101\/2020.03.25.008482","abstract":"SARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with over 400,000 recorded COVID-19 cases and greater than 19,000 recorded deaths by March 24th, 2020 (www.WHO.org) (1). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2 (2). Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs (3). Rapid development and human testing of potential antivirals is greatly needed. A potentially quicker way to test compounds with antiviral activity is through drug re-purposing (2, 4). Numerous drugs are already approved for use in humans and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to test in COVID-19 patients. Here, we present data on 20 FDA approved drugs tested for antiviral activity against SARS-CoV-2 that we have previously found to inhibit SARS-CoV and MERS-CoV (4). We find that 17 of these also inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. From these we specifically followed up with hydroxychloroquine sulfate and chloroquine phosphate.","type":"Research","database":"BioRxiv","created":"2020-03-26"},{"id":173,"name":"The transmembrane serine protease inhibitors are potential antiviral drugs for 2019-nCoV targeting the insertion sequence-induced viral infectivity enhancement","author":"Tong Meng, Hao Cao, Hao Zhang, Zijian Kang, Da Xu, Haiyi Gong, Jing Wang, Zifu Li, Xingang Cui, Huji Xu, Haifeng Wei, Xiuwu Pan, Rongrong Zhu, Jianru Xiao, Wang Zhou, Liming Cheng, Jianmin Liu","doi":"10.1101\/2020.02.08.926006","abstract":"At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China1, even more spread than SARS-CoV infection2. The entry of SARS-CoV into host cells mainly depends on the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion3,4. The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear5,6. Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1\/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.","type":"Research","database":"BioRxiv","created":"2020-02-10"},{"id":171,"name":"Nelfinavir was predicted to be a potential inhibitor of 2019 nCov main protease by an integrative approach combining homology modelling, molecular doc","author":"Zhijian Xu, Cheng Peng, Yulong Shi, Zhengdan Zhu, Kaijie Mu, Xiaoyu Wang, Weiliang Zhu","doi":"10.1101\/2020.01.27.921627","abstract":"2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov Mpro is a potential drug target to combat the virus. We built homology models based on SARS Mpro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known Mpro ligands, 4 drugs were selected for binding free energy calculations. Both MM\/GBSA and SIE methods voted for nelfinavir, with the binding free energy of -24.69{+\/-}0.52 kcal\/mol and -9.42{+\/-}0.04 kcal\/mol, respectively. Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov Mpro.","type":"Research","database":"BioRxiv","created":"2020-01-27"},{"id":170,"name":"Protective Population Behavior Change in Outbreaks of Emerging Infectious Disease","author":"Evans K. Lodge, Annakate M. Schatz, John M. Drake","doi":"10.1101\/2020.01.27.921536","abstract":"During outbreaks of emerging infections, the lack of effective drugs and vaccines increases reliance on non-pharmacologic public health interventions and behavior change to limit human-to-human transmission. Interventions that increase the speed with which infected individuals remove themselves from the susceptible population are paramount, particularly isolation and hospitalization. Ebola virus disease (EVD), Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS) are zoonotic viruses that have caused significant recent outbreaks with sustained human-to-human transmission. This investigation quantified changing mean removal rates (MRR) and days from symptom onset to hospitalization (DSOH) of infected individuals from the population in seven different outbreaks of EVD, SARS, and MERS, to test for statistically significant differences in these metrics between outbreaks. We found that epidemic week and viral serial interval were correlated with the speed with which populations developed and maintained health behaviors in each outbreak.","type":"Research","database":"BioRxiv","created":"2020-01-27"},{"id":169,"name":"Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines","author":"Xin Liu, Xiu-Jie Wang","doi":"10.1101\/2020.01.29.924100","abstract":"Starting from December 2019, a novel coronavirus, named 2019-nCoV, was found to cause Severe Acute Respiratory (SARI) symptoms and rapid pandemic in China. With the hope to identify candidate drugs for 2019-nCoV, we adopted a computational approach to screen for available commercial medicines which may function as inhibitors for the Mpro of 2019-nCoV. Up to 10 commercial medicines that may form hydrogen bounds to key residues within the binding pocket of 2019-nCoV Mpro were identified, which may have higher mutation tolerance than lopinavir\/ritonavir and may also function as inhibitors for other coronaviruses with similar Mpro binding sites and pocket structures.","type":"Research","database":"BioRxiv","created":"2020-01-28"},{"id":168,"name":"Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening","author":"Yan Li, Jinyong Zhang, Ning Wang, Haibo Li, Yun Shi, Gang Guo, Kaiyun Liu, Hao Zeng, Quanming Zou","doi":"10.1101\/2020.01.28.922922","abstract":"2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic. The main protease of SARS-CoV is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development. In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV main protease by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV.","type":"Research","database":"BioRxiv","created":"2020-01-28"},{"id":167,"name":"Nucleotide Analogues as Inhibitors of Viral Polymerases","author":"Jingyue Ju, Shiv Kumar, Xiaoxu Li, Steffen Jockusch, James J. Russo","doi":"10.1101\/2020.01.30.927574","abstract":"Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir\/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.","type":"Research","database":"BioRxiv","created":"2020-01-30"},{"id":166,"name":"Predicting commercially available antiviral drugs that may act on the novel coronavirus (2019-nCoV), Wuhan, China through a drug-target interaction de","author":"Bo Ram Beck, Bonggun Shin, Yoonjung Choi, Sungsoo Park, Keunsoo Kang","doi":"10.1101\/2020.01.31.929547","abstract":"The infection of a novel coronavirus found in Wuhan of China (2019-nCoV) is rapidly spreading, and the incidence rate is increasing worldwide. Due to the lack of effective treatment options for 2019-nCoV, various strategies are being tested in China, including drug repurposing. In this study, we used our pretrained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of 2019-nCoV. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing a inhibitory potency with Kd of 94.94 nM against the 2019-nCoV 3C-like proteinase, followed by efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM). Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd < 1000 nM. In addition, we also found that several antiviral agents, such as Kaletra, could be used for the treatment of 2019-nCoV, although there is no real-world evidence supporting the prediction. Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for 2019-nCoV.","type":"Research","database":"BioRxiv","created":"2020-02-01"},{"id":165,"name":"Genome Detective Coronavirus Typing Tool for rapid identification and characterization of novel coronavirus genomes","author":"Sara Cleemput, Wim Dumon, Vagner Fonseca, Wasim Abdool Karim, Marta Giovanetti, Luiz Carlos Alcantara, Koen Deforche, Tulio de Oliveira","doi":"10.1101\/2020.01.31.928796","abstract":"SummaryGenome Detective is a web-based, user-friendly software application to quickly and accurately assemble all known virus genomes from next generation sequencing datasets. This application allows the identification of phylogenetic clusters and genotypes from assembled genomes in FASTA format. Since its release in 2019, we have produced a number of typing tools for emergent viruses that have caused large outbreaks, such as Zika and Yellow Fever Virus in Brazil. Here, we present The Genome Detective Coronavirus Typing Tool that can accurately identify novel coronavirus (2019-nCoV) sequences isolated in China and around the world. The tool can accept up to 2,000 sequences per submission and the analysis of a new whole genome sequence will take approximately one minute. The tool has been tested and validated with hundreds of whole genomes from ten coronavirus species, and correctly classified all of the SARS-related coronavirus (SARSr-CoV) and all of the available public data for 2019-nCoV. The tool also allows tracking of new viral mutations as the outbreak expands globally, which may help to accelerate the development of novel diagnostics, drugs and vaccines.\r\n\r\nAvailabilityAvailable online: https:\/\/www.genomedetective.com\/app\/typingtool\/cov\r\n\r\n* Contactkoen@emweb.be and deoliveira@ukzn.ac.za\r\n\r\nSupplementary informationSupplementary data is available online.","type":"Research","database":"BioRxiv","created":"2020-02-01"},{"id":164,"name":"Molecular Modeling Evaluation of the Binding Abilities of Ritonavir and Lopinavir to Wuhan Pneumonia Coronavirus Proteases","author":"Shen Lin, Runnan Shen, Xushun Guo","doi":"10.1101\/2020.01.31.929695","abstract":"Three anti-HIV drugs, ritonavir, lopinavir and darunavir, might have therapeutic effect on coronavirus disease 2019 (COVID-19). In this study, the structure models of two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteases, coronavirus endopeptidase C30 (CEP_C30) and papain like viral protease (PLVP), were built by homology modeling. Ritonavir, lopinavir and darunavir were then docked to the models, respectively, followed by energy minimization of the protease-drug complexes. In the simulations, ritonavir can bind to CEP_C30 most suitably, and induce significant conformation changes of CEP_C30; lopinavir can also bind to CEP_C30 suitably, and induce significant conformation changes of CEP_C30; darunavir can bind to PLVP suitably with slight conformation changes of PLVP. It is suggested that the therapeutic effect of ritonavir and lopinavir on COVID-19 may be mainly due to their inhibitory effect on CEP_C30, while ritonavir may have stronger efficacy; the inhibitory effect of darunavir on SARS-CoV-2 and its potential therapeutic effect may be mainly due to its inhibitory effect on PLVP.","type":"Research","database":"BioRxiv","created":"2020-02-02"},{"id":163,"name":"Machine intelligence design of 2019-nCoV drugs","author":"Kaifu Gao, Duc Duy Nguyen, Rui Wang, Guo-Wei Wei","doi":"10.1101\/2020.01.30.927889","abstract":"Wuhan coronavirus, called 2019-nCoV, is a newly emerged virus that infected more than 9692 people and leads to more than 213 fatalities by January 30, 2020. Currently, there is no effective treatment for this epidemic. However, the viral protease of a coronavirus is well-known to be essential for its replication and thus is an effective drug target. Fortunately, the sequence identity of the 2019-nCoV protease and that of severe-acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. We show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which means all potential anti-SARS-CoV chemotherapies are also potential 2019-nCoV drugs. Here, we report a family of potential 2019-nCoV drugs generated by a machine intelligence-based generative network complex (GNC). The potential effectiveness of treating 2019-nCoV by using some existing HIV drugs is also analyzed.","type":"Research","database":"BioRxiv","created":"2020-02-03"},{"id":162,"name":"Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection","author":"Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, Jiabin Cai, Jue Fan, Fei Lan","doi":"10.1101\/2020.02.03.931766","abstract":"A newly identified coronavirus, 2019-nCoV, has been posing significant threats to public health since December 2019. ACE2, the host cell receptor for severe acute respiratory syndrome coronavirus (SARS), has recently been demonstrated in mediating 2019-nCoV infection. Interestingly, besides the respiratory system, substantial proportion of SARS and 2019-nCoV patients showed signs of various degrees of liver damage, the mechanism and implication of which have not yet been determined. Here, we performed an unbiased evaluation of cell type specific expression of ACE2 in healthy liver tissues using single cell RNA-seq data of two independent cohorts, and identified specific expression in cholangiocytes. The results indicated that virus might directly bind to ACE2 positive cholangiocytes but not necessarily hepatocytes. This finding suggested the liver abnormalities of SARS and 2019-nCoV patients may not be due to hepatocyte damage, but cholangiocyte dysfunction and other causes such as drug induced and systemic inflammatory response induced liver injury. Our findings indicate that special care of liver dysfunction should be installed in treating 2019-nCoV patients during the hospitalization and shortly after cure.","type":"Research","database":"BioRxiv","created":"2020-02-03"},{"id":161,"name":"Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication","author":"Linlin Zhang, Daizong Lin, Yuri Kusov, Yong Nian, Qingjun Ma, Jiang Wang, Albrecht von Brunn, Pieter Leyssen, Kristina Lanko, Johan Neyts, Adriaan de Wilde, Eric J. Snijder, Hong Liu, Rolf Hilgenfeld","doi":"10.1101\/2020.02.10.936898","abstract":"The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued structure-based design of peptidomimetic -ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease:inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the -ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against Middle East Respiratory Syndrome coronavirus.","type":"Research","database":"BioRxiv","created":"2020-02-09"},{"id":160,"name":"Potentially highly potent drugs for 2019-nCoV","author":"Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei","doi":"10.1101\/2020.02.05.936013","abstract":"The World Health Organization (WHO) has declared the 2019 novel coronavirus (2019-nCoV) infection outbreak a global health emergency. Currently, there is no effective anti-2019-nCoV medication. The sequence identity of the 3CL proteases of 2019-nCoV and SARS is 96%, which provides a sound foundation for structural-based drug repositioning (SBDR). Based on a SARS 3CL protease X-ray crystal structure, we construct a 3D homology structure of 2019-nCoV 3CL protease. Based on this structure and existing experimental datasets for SARS 3CL protease inhibitors, we develop an SBDR model based on machine learning and mathematics to screen 1465 drugs in the DrugBank that have been approved by the U.S. Food and Drug Administration (FDA). We found that many FDA approved drugs are potentially highly potent to 2019-nCoV.","type":"Research","database":"BioRxiv","created":"2020-02-12"},{"id":159,"name":"X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of \u03b1-Ketoamide Inhibitors","author":"Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Ute Curth, Christian Drosten, Lucie Sauerhering, Stephan Becker, Katharina Rox, Rolf Hilgenfeld","doi":"10.1126\/science.abb3405","abstract":"The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, 3CLpro), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an \u03b1-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.","type":"Research","database":"BioRxiv","created":"2020-02-19"},{"id":158,"name":"Functional pangenome analysis provides insights into the origin, function and pathways to therapy of SARS-CoV-2 coronavirus","author":"Intikhab alam, Allan Kamau, Maxat Kulmanov, Stefan T. Arold, Arnab Pain, Takashi Gojobori, Carlos M. Duarte","doi":"10.1101\/2020.02.17.952895","abstract":"The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells1. The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar2, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-23. Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS)4-6, the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection7,8. However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride9,10) or the PBM (SB2035805), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.","type":"Research","database":"BioRxiv","created":"2020-02-20"},{"id":157,"name":"Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV)","author":"Jiahua He, Huanyu Tao, Yumeng Yan, Sheng-You Huang, Yi Xiao","doi":"10.1101\/2020.02.17.952903","abstract":"Since December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019-nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent with the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.","type":"Research","database":"BioRxiv","created":"2020-02-20"},{"id":155,"name":"Increasing Host Cellular Receptor--Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection","author":"Pei-Hui Wang, Yun Cheng","doi":"10.1101\/2020.02.24.963348","abstract":"The ongoing outbreak of a new coronavirus (2019-nCoV) causes an epidemic of acute respiratory syndrome in humans. 2019-nCoV rapidly spread to national regions and multiple other countries, thus, pose a serious threat to public health. Recent studies show that spike (S) proteins of 2019-nCoV and SARS-CoV may use the same host cell receptor called angiotensin-converting enzyme 2 (ACE2) for entering into host cells. The affinity between ACE2 and 2019-nCoV S is much higher than ACE2 binding to SARS-CoV S protein, explaining that why 2019-nCoV seems to be more readily transmitted from the human to human. Here, we reported that ACE2 can be significantly upregulated after infection of various viruses including SARS-CoV and MERS-CoV. Basing on findings here, we propose that coronavirus infection can positively induce its cellular entry receptor to accelerate their replication and spread, thus drugs targeting ACE2 expression may be prepared for the future emerging infectious diseases caused by this cluster of viruses.","type":"Research","database":"BioRxiv","created":"2020-02-26"},{"id":154,"name":"Spike protein binding prediction with neutralizing antibodies of SARS-CoV-2","author":"Tamina Park, Sang-Yeop Lee, Seil Kim, Mi Jeong Kim, Hong Gi Kim, Sangmi Jun, Seung Il Kim, Bum Tae Kim, Edmond Changkyun Park, Daeui Park","doi":"10.1101\/2020.02.22.951178","abstract":"Coronavirus disease 2019 (COVID-19) is a new emerging human infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, also previously known as 2019-nCoV), originated in Wuhan seafood and animal market, China. Since December 2019, more than 69,000 cases of COVID-19 have been confirmed in China and quickly spreads to other counties. Currently, researchers put their best efforts to identify effective drugs for COVID-19. The neutralizing antibody, which binds to viral capsid in a manner that inhibits cellular entry of virus and uncoating of the genome, is the specific defense against viral invaders. In this study, we investigate to identify neutralizing antibodies that can bind to SARS-CoV-2 Sipke (S) protein and interfere with the interaction between viral S protein and a host receptor by bioinformatic methods. The sequence analysis of S protein showed two major differences in the RBD region of the SARS-CoV-2 S protein compared to SARS-CoV and SARS-CoV related bat viruses (btSARS-CoV). The insertion regions were close to interacting residues with the human ACE2 receptor. Epitope analysis of neutralizing antibodies revealed that SARS-CoV neutralizing antibodies used conformational epitopes, whereas MERS-CoV neutralizing antibodies used a common linear epitope region, which contributes to form the {beta}-sheet structure in MERS-CoV S protein and deleted in SARS-CoV-2 S protein. To identify effective neutralizing antibodies for SARS-CoV-2, the binding affinities of neutralizing antibodies with SARS-CoV-2 S protein were predicted and compared by antibody-antigen docking simulation. The result showed that CR3022 neutralizing antibody from human may have higher binding affinity with SARS-CoV-2 S protein than SARS-CoV S protein. We also found that F26G19 and D12 mouse antibodies could bind to SARS-CoV S protein with high affinity. Our findings provide crucial clues towards the development of antigen diagnosis, therapeutic antibody, and the vaccine against SARS-CoV-2.","type":"Research","database":"BioRxiv","created":"2020-02-26"},{"id":153,"name":"Designing of a next generation multiepitope based vaccine (MEV) against SARS-COV-2: Immunoinformatics and in silico approaches","author":"Muhammad Tahir ul Qamar, Abdur Rehman, Usman Ali Ashfaq, Muhammad Qasim Awan, Israr Fatima, Farah Shahid, Ling-Ling Chen","doi":"10.1101\/2020.02.28.970343","abstract":"Coronavirus disease 2019 (COVID-19) associated pneumonia caused by severe acute respiratory coronavirus 2 (SARS-COV-2) was first reported in Wuhan, China in December 2019. Till date, no vaccine or completely effective drug is available to cure COVID-19. Therefore, an effective vaccine against SARS-COV-2 is crucially needed. This study was conducted to design an effective multiepitope based vaccine (MEV) against SARS-COV-2. Seven antigenic proteins were taken as targets and different epitopes (B-cell, T-cell and IFN-{gamma} inducing) were predicted. Highly antigenic and overlapping epitopes were shortlisted. Selected epitopes indicated significant interactions with the HLA-binding alleles and 99.29% coverage of the worlds population. Finally, 505 amino acids long MEV was designed by connecting sixteen MHC class I and eleven MHC class II epitopes with suitable linkers and adjuvant. Linkers and adjuvant were added to enhance the immunogenicity response of the MEV. The antigenicity, allergenicity, physiochemical properties and structural details of MEV were analyzed in order to ensure safety and immunogenicity. MEV construct was non-allergenic, antigenic, stable and flexible. Molecular docking followed by molecular dynamics (MD) simulation analysis, demonstrated a stable and strong binding affinity of MEV with human pathogenic toll-like receptors (TLR), TLR3 and TLR8. Codon optimization and in silico cloning of MEV ensured increased expression in the Escherichia coli K-12 system. Designed MEV in present study could be a potential candidate for further vaccine production process against COVID-19. However, to ensure its safety and immunogenic profile, the proposed MEV needs to be experimentally validated.","type":"Research","database":"BioRxiv","created":"2020-03-01"},{"id":152,"name":"Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19","author":"Meehyun Ko, So Young Chang, Soo Young Byun, Inhee Choi, Anne-Laure Pham Hung d\u2019Alexandry d\u2019Orengiani, David Shum, Ji-Young Min, Marc P. Windisch","doi":"10.1101\/2020.02.25.965582","abstract":"In 2015, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) reached the Republic of Korea through nosocomial transmission and was the largest epidemic outside of the Arabian Peninsula. To date, despite various strategies to identify CoV interventions, only limited therapeutic options are available. To address these unmet medical needs, we used a South Korean MERS-CoV clinical isolate and screened 5,406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactive molecules, for their activity against the isolate. The primary assay confirmed 221 hits by dose-response curve analysis and identified 54 hits with a therapeutic index (TI) greater than 6. Time-of-addition studies with 12 FDA-approved drugs demonstrated that 8 and 4 therapeutics act on the early and late stages of the viral life cycle, respectively. Among the drugs were e.g., three cardiotonic agents (ouabain, digitoxin, digoxin) with a TI greater than 100, an anti-malaria drug (atovaquone; TI >34), an inhalable corticosteroid (ciclesonide; TI >6), etc. Together, our results identify potential therapeutic options for treating MERS-CoV infections and could provide a basis for agents against a wider range of coronavirus-related illnesses, including the currently emerging Coronavirus Disease 2019 (COVID-19) outbreak.","type":"Research","database":"BioRxiv","created":"2020-03-01"},{"id":151,"name":"Molecular Dynamics Simulations Indicate the COVID-19 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design","author":"Maria Bz\u00f3wka, Karolina Mitusi\u0144ska, Agata Raczy\u0144ska, Aleksandra Samol, Jack Tuszy\u0144ski, Artur G\u00f3ra","doi":"10.1101\/2020.02.27.968008","abstract":"The coronavirus outbreak took place in December 2019 and continues to spread worldwide. In the absence of an effective vaccine, inhibitor repurposing may seem a fruitful attempt. Here, we compared Mpros from SARS-CoV-2 and SARS-CoV. Despite a high level of sequence similarity, the binding sites of analysed proteins show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, the analysis of the pockets conformational changes during the simulation time indicates their flexibility, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the SARS-CoV-2 Mpro with respect to mutations of the binding cavity and adjacent flexible loops indicates that the proteins mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.","type":"Research","database":"BioRxiv","created":"2020-03-01"},{"id":150,"name":"The within-host viral kinetics of SARS-CoV-2","author":"Chentong Li, Jinhu Xu, Jiawei Liu, Yicang Zhou","doi":"10.1101\/2020.02.29.965418","abstract":"In this work, we use a within-host viral dynamic model to describe the SARS-CoV-2 kinetics in host. Chest radiograph score data are used to estimate the parameters of that model. Our result shows that the basic reproductive number of SARS-CoV-2 in host growth is around 3.79. Using the same method we also estimate the basic reproductive number of MERS virus is 8.16 which is higher than SARS-CoV-2. The PRCC method is used to analyze the sensitivities of model parameters and the drug effects on virus growth are also implemented to analyze the model.","type":"Research","database":"BioRxiv","created":"2020-03-01"},{"id":149,"name":"Predictions for the binding domain and potential new drug targets of 2019-nCoV","author":"Zehua Zeng, Zhi Luo, Hongwu Du","doi":"10.1101\/2020.02.26.961938","abstract":"An outbreak of new SARS-like viral in Wuhan, China has been named 2019-nCoV. The current state of the epidemic is increasingly serious, and there has been the urgent necessity to develop an effective new drug. In previous studies, it was found that the conformation change in CTD1 was the region where SARS-CoV bound to human ACE2. Although there are mutations of the 2019-nCoV, the binding energy of ACE2 remains high. The surface glycoprotein of 2019-nCoV was coincident with the CTD1 region of the S-protein by comparing the I-TASSER prediction model with the actual SARS model, which suggests that 2019-nCoV may bind to the ACE2 receptor through conformational changes. Furthermore, site prediction on the surface glycoprotein of 2019-nCoV suggests some core amino acid area may be a novel drug target against 2019-nCoV.","type":"Research","database":"BioRxiv","created":"2020-03-01"},{"id":148,"name":"Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2","author":"Youngchang Kim, Robert Jedrzejczak, Natalia I. Maltseva, Michael Endres, Adam Godzik, Karolina Michalska, Andrzej Joachimiak","doi":"10.1101\/2020.03.02.968388","abstract":"Severe Acute Respiratory Syndrome Coronavirus 2 is rapidly spreading around the world. There is no existing vaccine or proven drug to prevent infections and stop virus proliferation. Although this virus is similar to human and animal SARS- and MERS-CoVs the detailed information about SARS-CoV-2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies and antivirals. We applied high-throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases to produce SARS-CoV-2 proteins and structures. Here we report the high-resolution crystal structure of endoribonuclease Nsp15\/NendoU from SARS-CoV-2 - a virus causing current world-wide epidemics. We compare this structure with previously reported models of Nsp15 from SARS and MERS coronaviruses.","type":"Research","database":"BioRxiv","created":"2020-03-02"},{"id":147,"name":"Isolation and characterization of SARS-CoV-2 from the first US COVID-19 patient","author":"Jennifer Harcourt, Azaibi Tamin, Xiaoyan Lu, Shifaq Kamili, Senthil Kumar. Sakthivel, Lijuan Wang, Janna Murray, Krista Queen, Brian Lynch, Brett Whitaker, Ying Tao,  Clinton R. Paden, Jing Zhang, Yan","doi":"10.1101\/2020.03.02.972935","abstract":"The etiologic agent of the outbreak of pneumonia in Wuhan China was identified as severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) in January, 2020. The first US patient was diagnosed by the State of Washington and the US Centers for Disease Control and Prevention on January 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens, and characterized the viral sequence, replication properties, and cell culture tropism. We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into two virus repositories, making it broadly available to the public health and research communities. We hope that open access to this important reagent will expedite development of medical countermeasures.\r\n\r\nArticle SummaryScientists have isolated virus from the first US COVID-19 patient. The isolation and reagents described here will serve as the US reference strain used in research, drug discovery and vaccine testing.","type":"Research","database":"BioRxiv","created":"2020-03-02"},{"id":145,"name":"Novel Immunoglobulin Domain Proteins Provide Insights into Evolution and Pathogenesis Mechanisms of SARS-Related Coronaviruses","author":"Yongjun Tan, Theresa Schneider, Matthew Leong, L Aravind, Dapeng Zhang","doi":"10.1101\/2020.03.04.977736","abstract":"A novel coronavirus (SARS-CoV-2) is the causative agent of an emergent severe respiratory disease (COVID-19) in humans that is threatening to result in a global health crisis. By using genomic, sequence, structural and evolutionary analysis, we show that Alpha- and Beta-CoVs possess several novel families of immunoglobulin (Ig) domain proteins, including ORF8 and ORF7a from SARS-related coronaviruses and two protein groups from certain Alpha-CoVs. Among them, ORF8 is distinguished in being rapidly evolving, possessing a unique insert and a hypervariable position among SARS-CoV-2 genomes in its predicted ligand-binding groove. We also uncover many Ig proteins from several metazoan viruses which are distinct in sequence and structure but share an architecture comparable to that of CoV Ig domain proteins. Hence, we propose that deployment of Ig domain proteins is a widely-used strategy by viruses, and SARS-CoV-2 ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts.","type":"Research","database":"BioRxiv","created":"2020-03-06"},{"id":144,"name":"Substrate specificity profiling of SARS-CoV-2 Mpro protease provides basis for anti-COVID-19 drug design","author":"Wioletta Rut, Katarzyna Groborz, Linlin Zhang, Xinyuanyuan Sun, Mikolaj Zmudzinski, Rolf Hilgenfeld, Marcin Drag","doi":"10.1101\/2020.03.07.981928","abstract":"In December 2019, the first cases of a novel coronavirus infection were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for COVID-19, therefore research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 Mpro protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 proteases, using natural and a large panel of unnatural amino acids. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.","type":"Research","database":"BioRxiv","created":"2020-03-07"},{"id":143,"name":"AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2","author":"Bowen Tang, Fengming He, Dongpeng Liu, Meijuan Fang, Zhen Wu, Dong Xu","doi":"10.1101\/2020.03.03.972133","abstract":"The focused drug repurposing of known approved drugs (such as lopinavir\/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https:\/\/github.com\/tbwxmu\/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.","type":"Research","database":"BioRxiv","created":"2020-03-07"},{"id":142,"name":"Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2","author":"Rui Xiong, Leike Zhang, Shiliang Li, Yuan Sun, Minyi Ding, Yong Wang, Yongliang Zhao, Yan Wu, Weijuan Shang, Xiaming Jiang, Jiwei Shan, Zihao Shen, Yi Tong, Liuxin Xu, Chen Yu, Yingle Liu, Gang Zou, D","doi":"10.1101\/2020.03.11.983056","abstract":"Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide\/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.","type":"Research","database":"BioRxiv","created":"2020-03-11"},{"id":141,"name":"Rigidity, normal modes and flexible motion of a SARS-CoV-2 (COVID-19) protease structure.","author":"Stephen A. Wells","doi":"10.1101\/2020.03.10.986190","abstract":"The rigidity and flexibility of two recently reported crystal structures (PDB entries 6Y2E and 6LU7) of a protease from the SARS-CoV-2 virus, the infectious agent of the COVID-19 respiratory disease, has been investigated using pebble-game rigidity analysis, elastic network model normal mode analysis, and all-atom geometric simulations. This computational investigation of the viral protease follows protocols that have been effective in studying other homodimeric enzymes. The protease is predicted to display flexible motions in vivo which directly affect the geometry of a known inhibitor binding site and which open new potential binding sites elsewhere in the structure. A database of generated PDB files representing natural flexible variations on the crystal structures has been produced and made available for download from an institutional data archive. This information may inform structure-based drug design and fragment screening efforts aimed at identifying specific antiviral therapies for the treatment of COVID-19.","type":"Research","database":"BioRxiv","created":"2020-03-11"},{"id":140,"name":"A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19","author":"Yiyue Ge, Tingzhong Tian, Suling Huang, Fangping Wan, Jingxin Li, Shuya Li, Hui Yang, Lixiang Hong, Nian Wu, Enming Yuan, Lili Cheng, Yipin Lei, Hantao Shu, Xiaolong Feng, Ziyuan Jiang, Ying Chi, Xili","doi":"10.1101\/2020.03.11.986836","abstract":"The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.","type":"Research","database":"BioRxiv","created":"2020-03-11"},{"id":136,"name":"Dark proteome of Newly Emerged SARS-CoV-2 in Comparison with Human and Bat Coronaviruses","author":"Rajanish Giri, Taniya Bhardwaj, Meenakshi Shegane, Bhuvaneshwari R. Gehi, Prateek Kumar, Kundlik Gadhave","doi":"10.1101\/2020.03.13.990598","abstract":"Recently emerged Wuhans novel coronavirus designated as SARS-CoV-2, a causative agent of coronavirus disease 2019 (COVID-19) is rapidly spreading its pathogenicity throughout the world now. More than 4000 mortalities have occurred worldwide till the writing of this article and this number is increasing every passing hour. World Health Organization (WHO) has declared it as a global public health emergency. The multiple sequence alignment data correlated with already published reports on SARS-CoV-2 indicated that it is closely related to Bat-Severe Acute Respiratory Syndrome like coronavirus (Bat CoV SARS-like) and well-studied Human SARS. In this study, we have exploited the complementary approach to examine the intrinsically disordered regions in proteome of SARS-CoV-2 using Bat SARS-like and Human SARS CoVs as comparative models. According to our findings, SARS-CoV-2 proteome contains a significant amount of ordered proteins except Nucleocapsid, Nsp8, and ORF6. Further, cleavage sites in replicase 1ab polyprotein are found to be highly disordered. We have extensively investigated the dark proteome in SARS-CoV-2 which will have implications for the structured and unstructured biology of SARS or SARS-like coronaviruses.\r\n\r\nSignificanceThe infection caused by Novel Coronavirus (SARS-CoV-2) is responsible for the current pandemic that cause severe respiratory disease and pneumonia-like infection in humans. Currently, there is no such in-depth information on protein structure and function available in public domain and no effective anti-viral or vaccines are available for the treatment of this infection. Our study provides comparative order and disorder-based proteome information with Human SARS and Bat CoV that may be useful for structure-based drug discovery.","type":"Research","database":"BioRxiv","created":"2020-03-13"},{"id":135,"name":"Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids","author":"Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, Youhua Xie, Xiaoyue Wang, Zhenghong Yuan, Junbo Liang, Rong Zhang, Xinhua Lin","doi":"10.1101\/2020.03.16.990317","abstract":"The newly emerged pandemic coronavirus, SARS-CoV-2, has posed a significant public health threat worldwide. However, the mode of virus transmission and tissue tropism is not well established yet. Recent findings of substantial liver damage in patients and ACE2+ cholangiocytes in healthy liver tissues prompted us to hypothesize that human liver ductal organoids could serve as a model to determine the susceptibility and mechanisms underlining the liver damage upon SARS-CoV-2 infection. By single-cell RNA sequencing, we found that long-term liver ductal organoid culture preserved the human specific ACE2+ population of cholangiocytes. Moreover, human liver ductal organoids were permissive to SARS-CoV-2 infection and support robust replication. Notably, virus infection impaired the barrier and bile acid transporting functions of cholangiocytes through dysregulation of genes involved in tight junction formation and bile acid transportation, which could explain the bile acid accumulation and consequent liver damage in patients. These results indicate that control of liver damage caused directly by viral infection should be valued in treating COVID-19 patients. Our findings also provide an application of human organoids in investigating the tropism and pathogenesis of SARS-CoV-2, which would facilitate novel drug discovery.","type":"Research","database":"BioRxiv","created":"2020-03-16"},{"id":134,"name":"Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target","author":"Yan Gao, Liming Yan, Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun, Zhenhua Ming, Lianqi Zhang, Ji Ge, Litao Zheng, Ying Zhang, Haofeng Wang, Yan Zhu, Chen Zhu, Tianyu Hu, Tian","doi":"10.1101\/2020.03.16.993386","abstract":"A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication\/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-[A]. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified {beta}-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication\/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp.\r\n\r\nOne Sentence SummaryStructure of 2019-nCov RNA polymerase.","type":"Research","database":"BioRxiv","created":"2020-03-16"},{"id":133,"name":"An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus","author":"Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Sch\u00e4fer, Kenneth H. Dinnon III, Stephanie A. Montgomery, Maria L. Agostini, Andrea J. Pruijss","doi":"10.1101\/2020.03.19.997890","abstract":"Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog {beta}-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (b-D-N4-hydroxycytidine-5-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis. The potency of NHC\/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.","type":"Research","database":"BioRxiv","created":"2020-03-19"},{"id":132,"name":"The first-in-class peptide binder to the SARS-CoV-2 spike protein","author":"G. Zhang, S. Pomplun, A. R. Loftis, A. Loas, B. L. Pentelute","doi":"10.1101\/2020.03.19.999318","abstract":"Coronavirus disease 19 (COVID-19) is an emerging global health crisis. With over 200,000 confirmed cases to date, this pandemic continues to expand, spurring research to discover vaccines and therapies. SARS-CoV-2 is the novel coronavirus responsible for this disease. It initiates entry into human cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor binding domain (RBD) of its spike protein (S). Disrupting the SARS-CoV-2-RBD binding to ACE2 with designer drugs has the potential to inhibit the virus from entering human cells, presenting a new modality for therapeutic intervention. Peptide-based binders are an attractive solution to inhibit the RBD-ACE2 interaction by adequately covering the extended protein contact interface. Using molecular dynamics simulations based on the recently solved ACE2 and SARS-CoV-2-RBD co-crystal structure, we observed that the ACE2 peptidase domain (PD) 1 helix is important for binding SARS-CoV-2-RBD. Using automated fast-flow peptide synthesis, we chemically synthesized a 23-mer peptide fragment of the ACE2 PD 1 helix composed entirely of proteinogenic amino acids. Chemical synthesis of this human derived sequence was complete in 1.5 hours and after work up and isolation >20 milligrams of pure material was obtained. Bio-layer interferometry revealed that this peptide specifically associates with the SARS-CoV-2-RBD with low nanomolar affinity. This peptide binder to SARS-CoV-2-RBD provides new avenues for COVID-19 treatment and diagnostic modalities by blocking the SARS-CoV-2 spike protein interaction with ACE2 and thus precluding virus entry into human cells.","type":"Research","database":"BioRxiv","created":"2020-03-19"},{"id":129,"name":"Replication of SARS-CoV-2 in human respiratory epithelium","author":"Aleksandra Milewska, Anna Kula-Pacurar, Jakub Wadas, Agnieszka Suder, Artur Szczepanski, Agnieszka Dabrowska, Katarzyna Owczarek, Marek Ochman, Tomasz Stacel, Zenon Rajfur, Pawel Labaj, Wojciech Brani","doi":"10.1101\/2020.03.20.999029","abstract":"SARS-CoV-2 emerged by the end of 2019 to rapidly spread in 2020. At present, it is of utmost importance to understand the virus biology and to rapidly assess the potential of existing drugs and develop new active compounds. While some animal models for such studies are under development, most of the research is carried out in the Vero E6 cells. Here, we propose fully differentiated human airway epithelium cultures as a model for studies on the SARS-CoV-2. Further, we also provide basic characteristics of the system.","type":"Research","database":"BioRxiv","created":"2020-03-20"},{"id":128,"name":"COVID-19 coronavirus vaccine design using reverse vaccinology and machine learning","author":"Edison Ong, Mei U Wong, Anthony Huffman, Yongqun He","doi":"10.1101\/2020.03.20.000141","abstract":"To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign reverse vaccinology tool and the newly developed Vaxign-ML machine learning tool to predict COVID-19 vaccine candidates. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and linear B-cell epitopes localized in specific locations and functional domains of the protein. By applying reverse vaccinology and machine learning, we predicted potential vaccine targets for effective and safe COVID-19 vaccine development. We then propose that an \"Sp\/Nsp cocktail vaccine\" containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.","type":"Research","database":"BioRxiv","created":"2020-03-20"},{"id":127,"name":"A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing","author":"David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Matthew J. O\u2019Meara, Jeffrey Z. Guo, Danielle L. Swaney, Tia A. Tummino, Ruth H\u00fcttenhain, Robyn M. Kaake, Alicia L. Ric","doi":"10.1101\/2020.03.22.002386","abstract":"An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and\/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.","type":"Research","database":"BioRxiv","created":"2020-03-21"},{"id":126,"name":"Emergence of SARS-CoV-2 through Recombination and Strong Purifying Selection","author":"Xiaojun Li, Elena E. Giorgi, Manukumar Honnayakanahalli Marichann, Brian Foley, Chuan Xiao, Xiang-Peng Kong, Yue Chen, Bette Korber, Feng Gao","doi":"10.1101\/2020.03.20.000885","abstract":"COVID-19 has become a global pandemic caused by a novel coronavirus SARS-CoV-2. Understanding the origins of SARS-CoV-2 is critical for deterring future zoonosis and for drug discovery and vaccine development. We show evidence of strong purifying selection around the receptor binding motif (RBM) in the spike gene and in other genes among bat, pangolin and human coronaviruses, indicating similar strong evolutionary constraints in different host species. We also demonstrate that SARS-CoV-2s entire RBM was introduced through recombination with coronaviruses from pangolins, possibly a critical step in the evolution of SARS-CoV-2s ability to infect humans. Similar purifying selection in different host species and frequent recombination among coronaviruses suggest a common evolutionary mechanism that could lead to new emerging human coronaviruses.\r\n\r\nOne Sentence SummaryExtensive Recombination and Strong Purifying Selection among coronaviruses from different hosts facilitate the emergence of SARS-CoV-2","type":"Research","database":"BioRxiv","created":"2020-03-21"},{"id":125,"name":"FEP-based screening prompts drug repositioning against COVID-19","author":"Zhe Li, Xin Li, Yi-You Huang, Yaoxing Wu, Lingli Zhou, Runduo Liu, Deyan Wu, Lei Zhang, Hao Liu, Ximing Xu, Yuxia Zhang, Jun Cui, Xin Wang, Hai-Bin Luo","doi":"10.1101\/2020.03.23.004580","abstract":"The new coronavirus COVID-19, also known as SARS-CoV-2, has infected more than 300,000 patients and become a global health emergency due to the very high risk of spread and impact of COVID-19. There are no specific drugs or vaccines against COVID-19, thus effective antiviral agents are still urgently needed to combat this virus. Herein, the FEP (free energy perturbation)-based screening strategy is newly derived as a rapid protocol to accurately reposition potential agents against COVID-19 by targeting viral proteinase Mpro. Restrain energy distribution (RED) function was derived to optimize the alchemical pathway of FEP, which greatly accelerated the calculations and first made FEP possible in the virtual screening of the FDA-approved drugs database. As a result, fifteen out of twenty-five drugs validated in vitro exhibited considerable inhibitory potencies towards Mpro. Among them, the most potent Mpro inhibitor dipyridamole potentially inhibited NF-{kappa}B signaling pathway and inflammatory responses, and has just finished the first round clinical trials. Our result demonstrated that the FEP-based screening showed remarkable advantages in prompting drug repositioning against COVID-19.","type":"Research","database":"BioRxiv","created":"2020-03-24"},{"id":124,"name":"Analysis of codon usage and evolutionary rates of the 2019-nCoV genes","author":"Maddalena Dilucca, Sergio Forcelloni, Athanasia Pavlopoulou, Alexandros G. Georgakilas, Andrea Giansanti","doi":"10.1101\/2020.03.25.006569","abstract":"Severe acute respiratory syndrome coronavirus 2 (2019-nCoV), which first broke out in Wuhan (China) in December of 2019, causes a severe acute respiratory illness with a mortality ranging from 3% to 6%. To better understand the evolution of the newly emerging 2019-nCoV, in this paper, we analyze the codon usage pattern of 2019-nCoV. For this purpose, we compare the codon usage of 2019-nCoV with that of other 30 viruses belonging to the subfamily of orthocoronavirinae. We found that 2019-nCoV shows a rich composition of AT nucleotides that strongly influences its codon usage, which appears to be not optimized to human host. Then, we study the evolutionary pressures influencing the codon usage and evolutionary rates of the sequences of five conserved genes that encode the corresponding proteins (viral replicase, spike, envelope, membrane and nucleocapsid) characteristic of coronaviruses. We found different patterns of both mutational bias and nature selection that affect the codon usage of these genes at different extents. Moreover, we show that the two integral membrane proteins proteins (matrix and envelope) tend to evolve slowly by accumulating nucleotide mutations on their genes. Conversely, genes encoding nucleocapsid (N), viral replicase and spike proteins are important targets for the development of vaccines and antiviral drugs, tend to evolve faster as compared to other ones. Taken together, our results suggest that the higher evolutionary rate observed for these two genes could represent a major barrier in the development of antiviral therapeutics 2019-nCoV.","type":"Research","database":"BioRxiv","created":"2020-03-26"},{"id":123,"name":"Topoisomerase III-beta is required for efficient replication of positive-sense RNA viruses","author":"K. Reddisiva Prasanth, Minato Hirano, W. Samuel Fagg, Eileen T. McAnarney, Chao Shan, Xuping Xie, Adam Hage, Colette A. Pietzsch, Alexander Bukreyev, Ricardo Rajsbaum, Pei-Yong Shi, Mark T. Bedford, S","doi":"10.1101\/2020.03.24.005900","abstract":"Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-beta (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SARS-CoV-2. While there are no drugs that specifically inhibit this topoisomerase, we posit that TOP3B is an attractive anti-viral target.","type":"Research","database":"BioRxiv","created":"2020-03-26"},{"id":122,"name":"Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease","author":"Wenhao Dai, Bing Zhang, Xia-Ming Jiang, Haixia Su, Jian Li, Yao Zhao, Xiong Xie, Zhenming Jin, Jingjing Peng, Fengjiang Liu, Chunpu Li, You Li, Fang Bai, Haofeng Wang, Xi Chen, Xiaobo Cen, Shulei Hu, ","doi":"10.1101\/2020.03.25.996348","abstract":"SARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 M and 0.04 M respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 M and 0.33 M, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 [A] resolution, respectively. The crystal structures showed that 11a and 11b are irreversible, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds are promising drug leads with clinical potential that merits further studies.","type":"Research","database":"BioRxiv","created":"2020-03-27"},{"id":121,"name":"SARS-CoV-2 exhibits intra-host genomic plasticity and low-frequency polymorphic quasispecies","author":"Timokratis Karamitros, Gethsimani Papadopoulou, Maria Bousali, Anastasios Mexias, Sotiris Tsiodras, Andreas Mentis","doi":"10.1101\/2020.03.27.009480","abstract":"In December 2019, an outbreak of atypical pneumonia (Coronavirus disease 2019 -COVID-19) associated with a novel coronavirus (SARS-CoV-2) was reported in Wuhan city, Hubei province, China. The outbreak was traced to a seafood wholesale market and human to human transmission was confirmed. The rapid spread and the death toll of the new epidemic warrants immediate intervention. The intra-host genomic variability of SARS-CoV-2 plays a pivotal role in the development of effective antiviral agents and vaccines, but also in the design of accurate diagnostics. We analyzed NGS data derived from clinical samples of three Chinese patients infected with SARS-CoV-2, in order to identify small- and large-scale intra-host variations in the viral genome. We identified tens of low- or higher-frequency single nucleotide variations (SNVs) with variable density across the viral genome, affecting 7 out of 10 protein-coding viral genes. The majority of these SNVs corresponded to missense changes. The annotation of the identified SNVs but also of all currently circulating strain variations revealed colocalization of intra-host but also strain specific SNVs with primers and probes currently used in molecular diagnostics assays. Moreover, we de-novo assembled the viral genome, in order to isolate and validate intra-host structural variations and recombination breakpoints. The bioinformatics analysis disclosed genomic rearrangements over poly-A \/ poly-U regions located in ORF1ab and spike (S) gene, including a potential recombination hot-spot within S gene. Our results highlight the intra-host genomic diversity and plasticity of SARS-CoV-2, pointing out genomic regions that are prone to alterations. The isolated SNVs and genomic rearrangements, reflect the intra-patient capacity of the polymorphic quasispecies, which may arise rapidly during the outbreak, allowing immunological escape of the virus, offering resistance to anti-viral drugs and affecting the sensitivity of the molecular diagnostics assays.","type":"Research","database":"BioRxiv","created":"2020-03-27"},{"id":120,"name":"Site-specific N-glycosylation Characterization of Recombinant SARS-CoV-2 Spike Proteins using High-Resolution Mass Spectrometry","author":"Yong Zhang, Wanjun Zhao, Yonghong Mao, Shisheng Wang, Yi Zhong, Tao Su, Meng Gong, Xiaofeng Lu, Jingqiu Cheng, Hao Yang","doi":"10.1101\/2020.03.28.013276","abstract":"The global pandemic of severe acute pneumonia syndrome (COVID-19) caused by SARS-CoV-2 urgently calls for prevention and intervention strategies. The densely glycosylated spike (S) protein highly exposed on the viral surface is a determinant for virus binding and invasion into host cells as well as elicitation of a protective host immune response. Herein, we characterized the site-specific N-glycosylation of SARS-CoV-2 S protein using stepped collision energy (SCE) mass spectrometry (MS). Following digestion with two complementary proteases to cover all potential N-glycosylation sequons and integrated N-glycoproteomics analysis, we revealed the N-glycosylation profile of SARS-CoV-2 S proteins at the levels of intact N-glycopeptides and glycosites, along with the glycan composition and site-specific number of glycans. All 22 potential canonical N-glycosites were identified in S protein protomer. Of those, 18 N-glycosites were conserved between SARS-CoV and SARS-CoV-2 S proteins. Nearly all glycosites were preserved among the 753 SARS-CoV-2 genome sequences available in the public influenza database Global Initiative on Sharing All Influenza Data. By comparison, insect cell-expressed SARS-CoV-2 S protein contained 38 N-glycans, which were primarily assigned to the high-mannose type N-glycans, whereas the human cell-produced protein possessed up to 140 N-glycans largely belonging to the complex type. In particular, two N-glycosites located in the structurally exposed receptor-binding domain of S protein exhibited a relatively conserved N-glycan composition in human cells. This N-glycosylation profiling and determination of differences between distinct expression systems could shed light on the infection mechanism and promote development of vaccines and targeted drugs.","type":"Research","database":"BioRxiv","created":"2020-03-28"},{"id":119,"name":"Harnessing powers of genomics to build molecular maps of coronavirus targets in human cells: a guide for existing drug repurposing and experimental studies identifying candidate therapeutics to mitigate the pandemic COVID-19.","author":"Gennadi Glinsky","doi":"10.26434\/chemrxiv.12052512.v2","abstract":"Coronavirus pandemic COVID-19 caused by the newly emerged SARS-CoV-2 virus is rapidly spreading around the glove and entering the most dangerous acute phase of its evolution in the United States. Recent progress in defining genetic and molecular determinants mediating the SARS-CoV-2 entry into human cells (Walls et al., 2020) should facilitate development of targeted therapeutics and efficient vaccines. Here, human genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomics-guided maps of up-stream regulatory elements, their expression and functions in human body, including pathophysiologically-relevant cell types. Genes acting as repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1) were then employed to identify existing drugs that manifest gene expression signatures of the potential coronavirus infection mitigation agents. Using this strategy, Vitamin D and Quercetin have been identified as putative pandemic mitigation agents. Gene expression profiles of Vitamin D and Quercetin activities and their established safety records as over-the-counter medicinal substances suggest that they may represent viable candidates for further assessment and considerations of their potential utility as coronavirus pandemic mitigation agents. Notably, gene set enrichment analyses and expression profiling experiments identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of Testosterone versus Estradiol impacts on SCARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically-viable interventions to combat the pandemic.","type":"Research","database":"ChemRxiv","created":"2020-03-31"},{"id":117,"name":"Drug Repurposing Approach Targeted Against Main Protease of SARS-CoV-2 Exploiting \u2018Neighbourhood Behaviour\u2019 in 3D Protein Structural Space and 2D Chemical Space of Small Molecules","author":"Sohini Chakraborti Narayanaswamy Srinivasan","doi":"10.26434\/chemrxiv.12057846.v1","abstract":"The current global crisis due to COVID-19 has almost brought normal life to standstill in most parts of the world. With our research interest on repurposing known drugs\/drug candidates targeting various diseases, we decided to analyse the available data on the deadly pathogen that has already taken thousands of lives since its outbreak in China in December 2019. Our host institute is now shutdown and we are confining ourselves to our homes with limited access to computational resources. Using a simple in silico approach based on the principle of \u2018neighbourhood behaviour\u2019 in three-dimensional (3D) space and two-dimensional (2D) space of protein and small molecules respectively, we have identified potential drugs\/drug candidates which can be repurposed against protein targets encoded by the SARS-CoV-2 genome. Based on our preliminary analysis, we have so far prioritized more than 20 known drugs\/drug candidates which might elucidate anti-coronavirus properties by binding to main protease of the pathogen. These drugs belong to diverse therapeutic areas such as antiviral, anticancer, antibacterial agents etc. Notably, apart from many synthetic molecules, our analysis also hints that phytochemicals obtained from vinca plant (vinca alkaloids) and camptotheca tree (camptothecin and its derivatives) have the potential to bind to main protease of SARS-CoV-2. In-depth investigation on our findings are currently on-going. Here we are presenting the results we obtained so far. The sole purpose of making these preliminary findings openly available to the community is for the experimental biologists and biomedical researchers to investigate our predictions in experimental set ups and for the clinicians to evaluate the potential of these findings for anti-COVID-19 treatment. Our findings should only be used for research purposes and we strongly urge that no individual should interpret these findings for any self-diagnosis or self-medication without the prior approval from competent international health\/medical regulatory agencies.","type":"Research","database":"ChemRxiv","created":"2020-04-02"},{"id":116,"name":"Harnessing Powers of Genomics to Build Molecular Maps of Coronavirus Targets in Human Cells: A Guide for Existing Drug Repurposing and Experimental St","author":"Gennadi Glinsky","doi":"10.26434\/chemrxiv.12052512.v1","abstract":"Coronavirus pandemic COVID-19 caused by the newly emerged SARS-CoV-2 virus is rapidly spreading around the glove and entering the most dangerous acute phase of its evolution in the United States. Recent progress in defining genetic and molecular determinants mediating the SARS-CoV-2 entry into human cells (Walls et al., 2020) should facilitate development of targeted therapeutics and efficient vaccines. Here, human genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomics-guided maps of up-stream regulatory elements, their expression and functions in human body, including pathophysiologically-relevant cell types. Genes acting as repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1) were then employed to identify existing drugs that manifest gene expression signatures of the potential coronavirus infection mitigation agents. Using this strategy, Vitamin D and Quercetin have been identified as putative pandemic mitigation agents. Gene expression profiles of Vitamin D and Quercetin activities and their established safety records as over-the-counter medicinal substances suggest that they may represent viable candidates for further assessment and considerations of their potential utility as coronavirus pandemic mitigation agents. Notably, gene set enrichment analyses and expression profiling experiments identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of Testosterone versus Estradiol impacts on SCARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically-viable interventions to combat the pandemic.","type":"Research","database":"ChemRxiv","created":"2020-03-31"},{"id":115,"name":"Chloroquine and Lopinavir (COVID-19 Drug Candidates) Signal Amplification by Reversible Exchange","author":"HyeJin Jeong Sein Min Heelim Chae Sara Kim Gunwoo Lee Sung Keon Namgoong Keunhong Jeong","doi":"10.26434\/chemrxiv.12055395.v1","abstract":"To overcome the recent coronavirus pneumonia (COVID-19), several drug candidates are suggested and tested for the latest clinical treatment. Chloroquine and lopinavir are showing definite effects after treatment. To understand more about those roles in molecular level and future application on NMR\/MRI, hyperpolarization technique can open new opportunities in the diagnosis and biomedical researches to cope with COVID-19. SABRE-based hyperpolarization studies on those two drug candidates are carried out and we observed hyperpolarized proton signals from the whole structures, which can be possible by unprecedented long-distance polarization transfer by para-hydrogen. Base on this result, future work on isotope labeling, and further polarization transfer on long T1 time nuclei including clinical perspectives will open a new door for overcoming this dreadful catastrophe.","type":"Other","database":"ChemRxiv","created":"2020-04-01"},{"id":114,"name":"In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19","author":"Yogesh Kumar Harvijay Singh","doi":"10.26434\/chemrxiv.12049590.v1","abstract":"The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global\r\npublic health emergency of unprecedented level. Therefore the need of a drug or vaccine that\r\ncounter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome\r\nof SARS-CoV-2 is translated into large polyprotein which further processed into different\r\nnonstructural proteins to form viral replication complex by virtue of virus specific proteases:\r\nmain protease (3-CL protease) and papain protease. This indispensable function of main protease\r\nin virus replication makes this enzyme a promising target for the development of inhibitors and\r\npotential treatment therapy for novel coronavirus infection. The recently concluded \u03b1-ketoamide\r\nligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.\r\nhas revealed the potential inhibitor binding mechanism and the determinants responsible for\r\ninvolved molecular interactions. Here, we have carried out a virtual screening and molecular\r\ndocking study of FDA approved drugs primarily targeted for other viral infections, to investigate\r\ntheir binding affinity in Mpro active site. Virtual screening has identified a number of antiviral\r\ndrugs, top ten of which on the basis of their bending energy score are further examined through\r\nmolecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir\r\nand Raltegravir among others binds in the active site of the protease with similar or higher\r\naffinity than the crystal bound inhibitor \u03b1-ketoamide. However, the in-vitro efficacies of the drug\r\nmolecules tested in this study, further needs to be corroborated by carrying out biochemical and\r\nstructural investigation. Moreover, this study advances the potential use of existing drugs to be\r\ninvestigated and used to contain the rapidly expanding SARS-CoV-2 infection.","type":"Research","database":"ChemRxiv","created":"2020-03-31"},{"id":111,"name":"Whole Genome Sequence Analysis and Homology Modelling of a 3C Like Peptidase and a Non-Structural Protein 3 of the SARS-CoV-2 Shows Protein Ligand Interaction with an Aza-Peptide and a Noncovalent Lead Inhibitor with Possible Antiviral Properties","author":"Arun Shanker Divya Bhanu Anjani Alluri","doi":"10.26434\/chemrxiv.11846943.v6","abstract":"The family of viruses belonging to Coronaviridae mainly consist of virulent pathogens that have a zoonotic property, Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) of this family have emerged before and now the SARS-CoV-2 has emerged in China. Characterization of spike glycoproteins, polyproteins and other viral proteins from viruses are important for vaccine development. Homology modelling of these proteins with known templates offers the opportunity to discover ligand binding sites and explore the possible antiviral properties of these protein ligand complexes. Any information emerging from these protein models can be used for vaccine development. In this study we did a complete bioinformatic analysis, sequence alignment, comparison of multiple sequences and homology modelling of the SARS-CoV-2 whole genome sequences, the spike protein and the polyproteins for homology with known proteins, we also analysed receptor binding sites in these models for possible binding with ligands that exhibit antiviral properties. Our results showed that the tertiary structure of the polyprotein isolate SARS-CoV-2_HKU-SZ-001_2020 had 98.94 percent identity with SARS-Coronavirus NSP12 bound to NSP7 and NSP8 co-factors. Our results indicate that a part of the viral genome (residues 3268 -3573 in Frame 2 with 306 amino acids) of the SARS-CoV-2 virus isolate Wuhan-Hu-1 (Genbank Accession Number MN908947.3) when modelled with template 2a5i of the PDB database had 96 percent identity with a 3C like peptidase of SARS-CoV which has ability to bind with Aza-Peptide Epoxide (APE) which is known for irreversible inhibition of SARS-CoV main peptidase. The part of the genome (residues 1568-1882 in Frame 2 with 315 amino acids) when modelled with template 3e9s of the PDB database had 82 percent identity with a papain-like protease\/deubiquitinase which when complexed with ligand GRL0617 acts as inhibitor which can block SARS-CoV replication. The regions studied was conserved in more than 90 genomes of SARS-CoV-2. It is possible that these viral inhibiters can be used for vaccine development for the SARS-CoV-2.","type":"Research","database":"ChemRxiv","created":"2020-02-12"},{"id":110,"name":"Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs","author":" Rimanshee Arya Amit Das Vishal Prashar Mukesh Kumar","doi":"10.26434\/chemrxiv.11860011.v2","abstract":"The cases of 2019 novel coronavirus (SARS-CoV-2) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any SARS-CoV-2 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs in silico. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3\/S4 pockets of the active site of the enzyme. In our docking studies, sixteen FDA approved drugs, including chloroquine and formoterol, was found to bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.","type":"Research","database":"ChemRxiv","created":"2020-02-18"},{"id":108,"name":"Targeted Oxidation Strategy (TOS) for Potential Inhibition of Coronaviruses by Disulfiram \u2014 a 70-Year Old Anti-Alcoholism Drug","author":" Luyan Xu Jiahui Tong Yiran Wu Suwen Zhao Bo-Lin Lin","doi":"10.26434\/chemrxiv.11936292.v1","abstract":"In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and 2019-nCoV. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of 2019-nCoV reminds us of the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a new targeted oxidation strategy (TOS II) leveraging non-covalent interactions potentially to oxidize and inhibit the activities of cytosolic thiol proteins via thiol\/thiolate oxidation to disulfide (TOD). Quantum mechanical calculations show encouraging results supporting the feasibility to selectively oxidize thiol of targeted proteins via TOS II even in relatively reducing cytosolic microenvironments. Molecular docking against the two thiol proteases Mpro and PLpro of 2019-nCoV provide evidence to support a TOS II mechanism for two experimentally identified anti-2019-nCoV disulfide oxidants: disulfiram and PX-12. Remarkably, disulfiram is an anti-alcoholism drug approved by FDA 70 years ago, thus it can be immediately used in phase III clinical trial for anti-2019-nCoV treatment. Finally, a preliminary list of promising TOS II drug candidates targeting the two thiol proteases of 2019-nCoV are proposed upon virtual screening of 32143 disulfides.","type":"Research","database":"ChemRxiv","created":"2020-03-04"},{"id":106,"name":"In Silico Guided Drug Repurposing to Combat SARS-CoV-2 by Targeting Mpro, the Key Virus Specific Protease","author":"Ruchi Rani Ankur Singh Akshay Pareek Shailly Tomar","doi":"10.26434\/chemrxiv.12210845.v1","abstract":"The reemergence of SARS-CoV named, as SARS-CoV-2 has been highly infectious and able to infect a large population around the globe. The World Health Organization (WHO) has declared this SARS-CoV-2 associated Coronavirus Disease 2019 (COVID-19) as pandemic. SARS-CoV-2 genome is translated into polyproteins and has been processed by its protease enzymes. 3CLprotease is named as main protease (Mpro) enzyme which cleaves nsp4-nsp16. This crucial role of Mpro makes this enzyme a prime and promising antiviral target. The drug repurposing is a fast alternative method than the discovery of novel antiviral molecules. We have used high-throughput virtual screening approach to examine FDA approved LOPAC1280 library against Mpro. Primary screening have identified few potential drug molecule for the target among which 10 molecules were studied further. Molecular docking of selected molecules was done to detailed study about their binding energy and binding modes. Positively, Etoposide, BMS_195614, KT185, Idarubicin and WIN_62577 were found interacting with substrate binding pocket of Mpro with higher binding energy. These molecules are being advanced by our group for in vitro and in vivo testing to study the efficacy of identified drugs. As per our understanding, these molecules have the potential to efficiently interrupt the viral life cycle and may reduce or eliminate the expeditious outspreading of SARS-CoV-2.","type":"Research","database":"ChemRxiv","created":"2020-03-25"},{"id":105,"name":"Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells","author":"Stefano Rensi, Russ B Altman, Tianyun Liu, Yu-Chen Lo, Greg McInnes, Alex Derry, Allison Keys","doi":"10.26434\/chemrxiv.12009582.v1","abstract":"The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.","type":"Research","database":"ChemRxiv","created":"2020-03-19"},{"id":104,"name":"On the Generation of Novel Ligands for SARS-CoV-2 Protease and ACE2 Receptor via Constrained Graph Variational Autoencoders","author":" Jasper Kyle Catapang Junie B. Billones","doi":"10.26434\/chemrxiv.12011157.v3","abstract":"SARS-CoV-2 has no known vaccine nor any effective treatment that has been released for clinical trials yet. This has ultimately paved the way for novel drug discovery approaches since although there are multiple efforts focused on drug repurposing of clinically-approved drugs for SARS-CoV-2, it is also worth considering that these existing drugs can be surpassed in effectivity by novel ones. This research focuses on the generation of novel candidate inhibitors via constrained graph variational autoencoders and the calculation of their Tanimoto similarities against existing drugs---repurposing these existing drugs and considering the novel ligands as possible SARS-CoV-2 main protease inhibitors and ACE2 receptor blockers by docking them through PyRx and ranking these ligands. Additionally, this research has successfully generated three novel ligands for the SARS-CoV-2 main protease and four novel ligands for the ACE2 receptor.","type":"Research","database":"ChemRxiv","created":"2020-03-19"},{"id":103,"name":"Shotgun Drug Repurposing Biotechnology to Tackle Epidemics and Pandemics","author":"William Mangione Zackary Falls Thomas Melendy Gaurav Chopra Ram Samudrala","doi":"10.26434\/chemrxiv.12045318.v1","abstract":"In this manuscript we highlight consensus between the list of drugs currently in clinical trials to treat COVID-19, the worldwide pandemic caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), and the list of predictions made using our shotgun drug discovery, repurposing, and design platform known as CANDO (Computational Analysis of Novel Drug Opportunities). We make the argument that increased funding and development for drug repurposing biotechnology like ours will help combat the inevitable pathogenic outbreaks of the future. ","type":"Comment","database":"ChemRxiv","created":"2020-03-30"},{"id":101,"name":"In-Silico Drug Designing of Novel Morpholino Based Physcion Drug Candidate and Investigation of Inhibition Effects on Covid-19 RNA Dependent - RNA Polymerase Non Structural Protein 12 (Nsp 12) with ADMET Study","author":"Poojasri Sargunam Sribal Sridharan","doi":"10.26434\/chemrxiv.12044847.v1","abstract":"Recent explosion of highly fatal pandemic corona virus Covid-19 in human population. The Covid-19 is a positive sense single stranded enveloped virus which belongs to the Coronaviridae family required non-structural proteins 12 (nsp12), a RNA dependent-RNA polymerase as an important machinery for the viral genome replication and transcription processes. There are various RNA polymerase inhibitors are currently using in clinical activities to treat Covid-19 infections but their treating efficacy is not up to much impressive particularly in aged people. In this study, we docked Morpholino based physcion drug candidate against RNA polymerase target (PDB ID : 6NUR). We designed drug candidate using Chemsketch software and further it was proceeded to molecular docking using AutoDock Vina 4.0 software. UCSF Chimera software was used for visualization of 3-Dimensional structure of ligand - protein docked pose. Moreover the docked drug candidate was checked for ADMET properties. Hence, this study supports the emergence of developing an efficient new drugs to combat Covid-19 infections. From this computational study we identified the designed drug candidate have high potential of inhibition of virus RNA Dependent - RNA polymerase minimum binding energy of - 8.76. To identify the inhibition potential of designed ligand, we used Remdesivir resulted minimum binding energy of - 7.25 as a positive control. These findings supports emergency discovery of anti-viral drug candidate to combat Covid-19 infections all over the world.","type":"Research","database":"ChemRxiv","created":"2020-03-29"},{"id":100,"name":"D3Similarity: A Ligand-Based Approach for Predicting Drug Targets and for Virtual Screening of Active Compounds Against COVID-19","author":"Zhengdan Zhu Xiaoyu Wang Yanqing Yang Xinben Zhang Kaijie Mu Yulong Shi Cheng Peng Zhijian Xu weiliang zhu","doi":"10.26434\/chemrxiv.11959323.v1","abstract":"Discovering efficient drugs and identifying target proteins are still an unmet but urgent need for curing COVID-19. Protein structure based docking is a widely applied approach for discovering active compounds against drug targets and for predicting potential targets of active compounds. However, this approach has its inherent deficiency caused by, e.g., various different conformations with largely varied binding pockets adopted by proteins, or the lack of true target proteins in the database. This deficiency may result in false negative results. As a complementary approach to the protein structure based platform for COVID-19, termed as D3Docking in our recent work, we developed the ligand-based method, named D3Similarity, which is based on the molecular similarity evaluation between the submitted molecule(s) and those in an active compound database. The database is constituted by all the reported bioactive molecules against the coronaviruses SARS, MERS and SARS-CoV-2, some of which have target or mechanism information but some don\u2019t. Based on the two-dimensional and three-dimensional similarity evaluation of molecular structures, virtual screening and target prediction could be performed according to similarity ranking results. With two examples, we demonstrated the reliability and efficiency of D3Similarity for drug discovery and target prediction against COVID-19. D3Similarity is available free of charge at https:\/\/www.d3pharma.com\/D3Targets-2019-nCoV\/D3Similarity\/index.php.","type":"Research","database":"ChemRxiv","created":"2020-03-09"},{"id":99,"name":"Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study","author":"Serdar Durdagi, Busecan Aksoydan, Berna Dogan, Kader Sahin, Aida Shahraki","doi":"10.26434\/chemrxiv.12032712.v1","abstract":"There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged preclinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against","type":"Research","database":"ChemRxiv","created":"2020-03-25"},{"id":98,"name":"Comparative Computational Study of SARS-CoV-2 Receptors Antagonists from Already Approved Drugs","author":"Micael Davi, Lima de Oliveira, Kelson Mota, Teixeira de Oliveira","doi":"10.26434\/chemrxiv.12044538.v1","abstract":"According to the World Health Organisation, on March 27, 2020, the number of confirmed cases of COVID-19 has already exceeded 509.000 with about of 23.000 deaths worldwide. Given this, the impact of COVID-19 on humanity cannot be overlooked, and basic research are urgently needed. This research aims to find antagonists already approved for another diseases, that may inhibit activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as modulate the ACE2 receptors, largely found in lung cells and reduce viral replication by inhibiting NSP12 RNA Polymerase. Docking molecular simulations were realized among a total of 28 ligands published in the literature against COVID-19. Docking studies were made with algorithm of AutoDock Vina 1.1.2 software. A structure-based virtual screening was performed with MTiOpenScreen. Subsequently, the physical-chemical and pharmacokinetic parameters were analyzed with SwissADME in order to select only the most promising ones. Finally, simulations of molecular dynamics with elapsed time of 4 nanoseconds (ns) were analysed in order to better understand the action of drugs to the detriment of the limitations of molecular docking. This work has shown that, in comparative terms, Simeprevir, Paritaprevir, Remdesivir and Baricitinib are currently among the most promising in remission of symptoms from the disease. Hydroxy-chloroquine, Chloroquine and Azithromicin were not showed effective, as monotherapies, against COVID-19 or lung cell receptors. Nevertheless, it has not been able to reach conclusive results due to the limitations of computational techniques that do not take into account numerous empirical parameters.","type":"Research","database":"ChemRxiv","created":"2020-03-29"},{"id":97,"name":"In Silico Exploration of Molecular Mechanism and Potency Ranking of Clinically Oriented Drugs for Inhibiting SARS-CoV-2\u2019s Main Protease","author":"Tien Huynh, haoran wang, Binquan Luan","doi":"10.26434\/chemrxiv.12045549.v1","abstract":"Currently, the new coronavirus disease 2019 (COVID-19) is a global pandemic without any well calibrated treatment. To inactivate the SARS-CoV-2 virus that causes COVID-19, the main protease (Mpro) that performs key biological functions in the virus has been the focus of extensive studies. With the fast-response experimental efforts, the crystal structures of Mpro of the SARS-CoV-2 virus have just become available recently. Herein, we theoretically investigated the binding mechanism between the Mpro's pocket and various marketed drug molecules being tested in clinics to fight COVID-19 that show promising outcomes. Combining all existing experiment results with our computational ones, we revealed an important ligand-binding mechanism for the Mpro that the binding stability of a ligand inside the Mpro pocket can be significantly improved if the partial ligand occupies the so-called \"anchor\" site of the Mpro. Along with the high-potent drugs\/molecules (such as nelfinavir and curcumin) revealed in this study, the newly discovered binding mechanism paves the way for further optimizations and designs of Mpro's inhibitors with a high binding affinity. ","type":"Research","database":"ChemRxiv","created":"2020-03-30"},{"id":95,"name":"Possible Drug Candidates for COVID-19","author":"Navan Chauhan","doi":"10.26434\/chemrxiv.11985231.v1","abstract":"COVID-19, has been officially labeled as a pandemic by the World Health Organisation. This paper presents cloperastine and vigabatrin as two possible drug candidates for combatting the disease along with the process by which they were discovered. The paper presents the discoveries made by using a connectivity map and the docking configurations used to simulate the docking.","type":"Research","database":"ChemRxiv","created":"2020-03-16"},{"id":94,"name":"Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning","author":"Ayman Farag Ping Wang Mahmoud Ahmed Hesham Sadek","doi":"10.26434\/chemrxiv.12003930.v1","abstract":"The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months. Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines. In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus. We started with structure based drug design by screening more than 2000 FDA approved drugs against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket focusing on two potential sites (central and terminal sites) to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substrate-binding pocket. The top hits bound to the central site of Mpro substrate-binding pocket include antiviral drugs such as Darunavir, Nelfinavir and Saquinavir, some of which are already being tested in Covid-19 patients. Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin. In addition, the top hits bound to the terminal site of Mpro substrate-binding pocket include the anti-asthma drug Montelukast and the anti-histaminic Fexofenadine among others. These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination.","type":"Research","database":"ChemRxiv","created":"2020-03-18"},{"id":93,"name":"In Silico Drug Repurposing for SARS-CoV-2 Main Proteinase and Spike Proteins","author":"Irene Maffucci, Alessandro Contini","doi":"10.1021\/acs.jproteome.0c00383","abstract":"The pandemic caused by SARS-CoV-2 is currently representing a major health and economic threat to humanity. So far, no specific treatment to this viral infection has been developed and the emergency still requires an efficient intervention. In this work, we used virtual screening to facilitate drug repurposing against SARS-CoV-2, targeting viral main proteinase and spike protein with 3000 existing drugs. We used a protocol based on a docking step followed by a short molecular dynamic simulation and rescoring by the Nwat-MMGBSA approach. Our results provide suggestions for prioritizing in vitro and\/or in vivo tests of already available compounds.","type":"Research","database":"PubMed","created":"2020-02-12"},{"id":92,"name":"Knowledge-Based Structural Models of SARS-CoV-2 Proteins and Their Complex with Potential Drugs","author":"Atsushi Hijikata Clara Shionyu-Mitsuyama Setsu Nakae Masafumi Shionyu Motonori Ota Shigehiko Kanaya Tsuyoshi Shirai","doi":"10.26434\/chemrxiv.12021330.v1","abstract":"The World Health Organization (WHO) has declared a pandemic of the 2019 novel cornavirus SARS-CoV-2 infection (COVID-19). There is, however, no confirmed anti-COVID-19 therapeutic currently. In order to assist structure-based discovery of repurposing drugs against this disease, knowledge-based models of SARS-CoV-2 proteins were constructed using MODELLER software, and their models were refined by PHENIX and COOT. The model quality was assessed with MolProbity. The ligand molecules in the template structures were compared with approved\/experimental drugs and components of natural medicines from the KEGG and KNApSAcK databases. The models suggested several drugs, such as carfilzomib, sinefungin, tecadenoson, and trabodenoson, as potential drugs for COVID-19.\r\n\r\n","type":"Research","database":"ChemRxiv","created":"2020-03-23"},{"id":91,"name":"Hydroxychloroquine and Azithromycin as a treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial","author":"Philippe GAUTRET, Jean Christophe LAGIER, Philippe PAROLA, Van Thuan HOANG, Line MEDDED, Morgan MAILHE, Barbara DOUDIER, Johan COURJON, Valerie GIORDANENGO, Vera ESTEVES VIEIRA, Herve TISSOT DUPONT, S","doi":"10.1101\/2020.03.16.20037135","abstract":"Background Chloroquine and Hydroxychloroquine have been found to be efficient on COV-19, and reported to be efficient in Chinese patients infected by this virus. We evaluate the role of Hydroxychloroquine on respiratory viral loads. Patients and methods Patients were included in a single arm protocol to receive 600mg of hydroxychloroquine daily and their viral load in nasal swabs was tested daily. Depending on their clinical presentation azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative control. Presence and absence of virus at Day-6 was considered the end point. Results Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D-6 compared to controls, and much lower than reported average carrying duration of untreated patients in the literature. Azithromycin added to Hydroxychloroquine was significantly more efficient for virus elimination. Conclusion : Hydroxychloroquine is significantly associated with viral load reduction\/disappearance in patients with COVID-19 and its effect is reinforced by Azithromycin.","type":"Research","database":"MedRxiv","created":"2020-03-19"},{"id":90,"name":"Network-based Drug Repurposing for Human Coronavirus","author":"Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin, Feixiong Cheng","doi":"10.1101\/2020.02.03.20020263","abstract":"Human Coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle east respiratory syndrome coronavirus (MERS-CoV), and 2019 novel coronavirus (2019-nCoV), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV has the highest nucleotide sequence identity with SARS-CoV (79.7%) among the six other known pathogenic HCoVs. Specifically, the envelope and nucleocapsid proteins of 2019-nCoV are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and known HCoV-host interactions in the human protein-protein interactome, we computationally identified 135 putative repurposable drugs for the potential prevention and treatment of HCoVs. In addition, we prioritized 16 potential anti-HCoV repurposable drugs (including melatonin, mercaptopurine, and sirolimus) that were further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. Finally, we showcased three potential drug combinations (including sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the Complementary Exposure pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human protein-protein interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations toward future clinical trials for HCoVs.","type":"Research","database":"MedRxiv","created":"2020-02-04"},{"id":89,"name":"ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection","author":"Caibin Fan, Kai Li, Yanhong Ding, Wei Lu Lu, Jianqing Wang","doi":"10.1101\/2020.02.12.20022418","abstract":"In December 2019 and January 2020, novel coronavirus (2019-nCoV) - infected pneumonia (NCIP) occurred in Wuhan, and has already posed a serious threat to public health. ACE2 (Angiotensin Converting Enzyme 2) has been shown to be one of the major receptors that mediate the entry of 2019-nCoV into human cells, which also happens in severe acute respiratory syndrome coronavirus (SARS). Several researches have indicated that some patients have abnormal renal function or even kidney damage in addition to injury in respiratory system, and the related mechanism is unknown. This arouses our interest in whether coronavirus infection will affect the urinary and male reproductive systems. Here in this study, we used the online datasets to analyze ACE2 expression in different human organs. The results indicate that ACE2 highly expresses in renal tubular cells, Leydig cells and cells in seminiferous ducts in testis. Therefore, virus might directly bind to such ACE2 positive cells and damage the kidney and testicular tissue of patients. Our results indicate that renal function evaluation and special care should be performed in 2019-nCoV patients during clinical work, because of the kidney damage caused by virus and antiviral drugs with certain renal toxicity. In addition, due to the potential pathogenicity of the virus to testicular tissues, clinicians should pay attention to the risk of testicular lesions in patients during hospitalization and later clinical follow-up, especially the assessment and appropriate intervention in young patients' fertility.","type":"Research","database":"MedRxiv","created":"2020-02-12"},{"id":88,"name":"The efficacy of convalescent plasma for the treatment of severe influenza","author":"Zhiheng Xu, Jianmeng Zhou, Yongbo Huang, Xuesong Liu, Yonghao Xu, Sibei Chen, Dongdong Liu, Zhimin Lin, Xiaoqing Liu, Yimin Li","doi":"10.1101\/2020.02.20.20025593","abstract":"Background. Administration of convalescent plasma may be of clinical benefit for treatment of severe acute viral respiratory infections. However, no clear evidence exists to support or oppose convalescent plasma use in clinical practice. We conducted a systematic review and meta-analysis to assess the evidence of randomized controlled trials (RCTs) in the convalescent plasma for the treatment of severe influenza. Methods. Healthcare databases were searched in February 2020. All records were screened against the eligibility criteria. Data extraction and risk of bias assessments were undertaken. The primary outcome was case fatality rates by influenza. Results. We identified 5 RCTs of severe influenza. The pooled analyses showed no evidence for a reduction in mortality (Odds Ratio (OR) 1.06; p = 0.87; I2 = 35%). We also found non significant reductions in days in ICU and hospital, and days on mechanical ventilation. There seemed to have a biological benefit of increasing HAI titer levels and decreasing influenza B virus loads and cytokines after convalescent plasma treatment. No serious adverse events was reported between two groups. Studies were commonly of low risk of bias with high quality. Conclusions. Convalescent plasma appears safe but may not reduce mortality in severe influenza. This therapy should be studied within the context of a well designed clinical trial for treatment of SARS Cov 2 infection.","type":"Research","database":"MedRxiv","created":"2020-02-22"},{"id":87,"name":"Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing\uff0cChina","author":"liu lei, Gao Jian-ya","doi":"10.1101\/2020.02.20.20025536","abstract":"Abstract BackgroundSince December 2019, Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-infected disease (Coronavirus Disease 2019COVID-19) emerged in Wuhan , Chinaand rapidly spread throughout Chinaeven throughout the world. We try to describe the epidemiological and clinical characteristics of COVID-19 in non-Wuhan areaand explore its effective treatment. MethodsRetrospective, single-center case series of the 51 hospitalized patients with confirmed COVID-19 at Chongqing University Three Gorges Hospital in Chongqing, China, from January 20 to February 3, 2020The discharge time was from January 29 to February 11, 2020. The main results and indicators of epidemiology, demography, clinical manifestation, laboratory examination, imaging data and treatment data of 51 patients with covid-19 were collected and analyzed. The changes of blood routine and biochemical indexes at discharge and admission were compared. Compare the clinical characteristics of severe patients (including severe and critical patients) and non- severe patients (general patients). Results Of 51 hospitalized patients with COVID-19, the median age was 45 years (interquartile range, 34-51; range, 16-68 years) and 32 (62.7%) were men.43(84.3%)patients had been to Wuhan or Other Hubei areas outside Wuhanand 4(7.7%) patients had a clear contact history of COVID-19 patients before the onset of the disease, and 4(7.7%) patients had no clear epidemiological history of COVID-19.Common symptoms included fever (43 [84.3%]), cough (38 [74.5%]) and fatigue (22 [43.1%]). Lymphopenia was observed in 26 patients (51.0%), and elevated C-reactive protein level in 32 patients (62.7%). Ground-glass opacity was the typical radiological finding on chest computed tomography (41 [80.4%])Local consolidation of pneumonia in some patients(17 [33.3%]).Most of the patients were treated with traditional Chinese medicine decoction (28 [54.9%])all of them received aerosol inhalation of recombinant human interferon a-1b for injection and oral antiviral therapy with Lopinavir and Ritonavir tablets (51 [100%]); Most of the patients were given Bacillus licheniformis capsules regulated intestinal flora treatment (44 [86.3%]). 10 patients (19.6%) received short-term (3-5 days) glucocorticoid treatment. Compared with non-severe patients (n = 44), severe patients (n = 7) were older (median age, 52 years vs 44 years), had a higher proportion of diabetes mellitus (4 [57.1%] vs 0 [0.0%]), most of them needed antibiotic treatment (7 [100%] vs 4 [9.1%], most of them needed nutritional diet (6 [85.7%) vs 0 [0.0%], and were more likely to have dyspnea (6 [85.7%] vs 5 [11.4%])most of them needed noninvasive mechanical ventilation (6 [85.7%] vs 0 [0.0%]). Except one patient died, the remaining 50 patients were discharged according to the discharge standard, the common clinical symptoms disappeared basically, the lymphocyte increased significantly (P=0.008), CRP decreased significantly (P <0.001). The median length of stay was 12 days (IQR, 9-13). ConclusionIn 51 single center cases confirmed as COVID-19 and discharged from the hospital, 13.7% of the patients were severe. The main clinical symptoms of patients with COVID-19 were fever, cough and astheniaSome patients had obvious dyspnea. They had clinical laboratory and radiologic characteristics. There is no specific drug treatment for the disease. For the treatment of COVID-19, in addition to oxygen inhalation and antiviral treatment, attention should be paid to the dialectical treatment of traditional Chinese medicine, regulation of intestinal flora, nutritional support treatment and other comprehensive treatment.","type":"Research","database":"MedRxiv","created":"2020-02-22"},{"id":86,"name":"Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia","author":"Hui Hui, Yingqian Zhang, Xin Yang, Xi Wang, Bingxi He, Li Li, Hongjun Li, Jie Tian, Yundai Chen","doi":"10.1101\/2020.02.24.20027052","abstract":"Objective: To investigate the correlation between clinical characteristics and cardiac injury of COVID-2019 pneumonia. Methods: In this retrospective, single-center study, 41 consecutive corona virus disease 2019 (COVID-2019) patients (including 2 deaths) of COVID-2019 in Beijing Youan Hospital, China Jan 21 to Feb 03, 2020, were involved in this study. The high risk factors of cardiac injury in different COVID-2019 patients were analyzed. Computed tomographic (CT) imaging of epicardial adipose tissue (EAT) has been used to demonstrate the cardiac inflammation of COVID-2019. ResultsOf the 41 COVID-2019 patients, 2 (4.88%), 32 (78.05%), 4 (9.75%) and 3 (7.32%) patients were clinically diagnosed as light, mild, severe and critical cases, according to the 6th guidance issued by the National Health Commission of China. 10 (24.4%) patients had underlying complications, such as hypertension, CAD, type 2 diabetes mellites and tumor. The peak value of TnI in critical patients is 40-fold more than normal value. 2 patients in the critical group had the onset of atrial fibrillation, and the peak heart rates reached up to 160 bpm. CT scan showed low EAT density in severe and critical patients. Conclusion: Our results indicated that cardiac injury of COVID-2019 was rare in light and mild patients, while common in severe and critical patients. Therefore, the monitoring of the heart functions of COVID-2019 patients and applying potential interventions for those with abnormal cardiac injury related characteristics, is vital to prevent the fatality.","type":"Research","database":"MedRxiv","created":"2020-02-26"},{"id":85,"name":"Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction","author":"Xiaoyan Liu, Zhe Li, Shuai Liu, Zhanghua Chen, Zhiyao Zhao, Yi-you Huang, Qingling Zhang, Jun Wang, Yinyi Shi, Yanhui Xu, Jing Sun, Huifang Xian, Rongli Fang, Fan Bai, Changxing Ou, Bei Xiong, Andrew ","doi":"10.1101\/2020.02.27.20027557","abstract":"The human coronavirus HCoV-19 infection can cause acute respiratory distress syndrome (ARDS), hypercoagulability, hypertension, extrapulmonary multiorgan dysfunction. Effective antiviral and anti-coagulation agents with safe clinical profiles are urgently needed to improve the overall prognosis. We screened an FDA approved drug library and found that an anticoagulant agent dipyridamole (DIP) suppressed HCoV-19 replication at an EC50 of 100 nM in vitro. It also elicited potent type I interferon responses and ameliorated lung pathology in a viral pneumonia model. In analysis of twelve HCoV-19 infected patients with prophylactic anti-coagulation therapy, we found that DIP supplementation was associated with significantly increased platelet and lymphocyte counts and decreased D-dimer levels in comparison to control patients. Two weeks after initiation of DIP treatment, 3 of the 6 severe cases (60%) and all 4 of the mild cases (100%) were discharged from the hospital. One critically ill patient with extremely high levels of D-dimer and lymphopenia at the time of receiving DIP passed away. All other patients were in clinical remission. In summary, HCoV-19 infected patients could potentially benefit from DIP adjunctive therapy by reducing viral replication, suppressing hypercoagulability and enhancing immune recovery. Larger scale clinical trials of DIP are needed to validate these therapeutic effects.","type":"Research","database":"MedRxiv","created":"2020-02-28"},{"id":84,"name":"Systematic Review of the Registered Clinical Trials of Coronavirus Diseases 2019 (COVID-19)","author":"Rui-fang Zhu, Ru-lu Gao, Sue-Ho Robert, Jin-ping Gao, Shi-gui Yang, Changtai Zhu","doi":"10.1101\/2020.03.01.20029611","abstract":"Background: Since the outbreak of coronavirus disease 2019 (COVID-19), many researchers in China have immediately carried out clinical research scheme of the COVID-19. But, there is still a lack of systematic review of registered clinical trials. Therefore, we conducted a systematic review of the clinical trials of COVID-19 to summarize the characteristics of the COVID-19 registered clinical trials. Methods: This study is based on the recommendations of the PRISMA in the Cochrane handbook. The databases from the Chinese Clinical Registration Center and the ClinicalTrials.gov were searched to collect the registered clinical trials of COVID-19. The retrieval inception date is February 9, 2020. Two researchers independently selected the literature based on inclusion and exclusion criteria, extracted data and evaluated the risk of bias. Results: A total of 75 registered clinical trials (63 interventional studies and 12 observational studies) of COVID-19 were obtained. A majority of clinical trials were sponsored by Chinese hospitals. Only 11 trials have begun to recruit patients, and none of the registered clinical trials had been completed; 34 trials were early clinical exploratory trials or in a pre-experiment stage, 15 trials belonged to phrase and 4 trials were phrase . The methods of intervention included traditional Chinese medicine involving 26 trials, Western medicine involving 30 trials, and integrated traditional Chinese medicine and Western medicine involving 19 trials. The subjects were mainly non-critical adult patients ([&ge;] 18 years old). The median sample size of the trials was 100 (IQR: 60 - 200), and the median execute time of the trials was 179 d (IQR: 94 - 366 d). The main outcomes were clinical observation and examinations. Overall, both the methodology quality of interventional trials and observational studies were low. Conclusions: Disorderly and intensive clinical trials of COVID-19 using traditional Chinese medicine and western medicine are ongoing or will being carried out in China. However, based on the low methodology quality and small sample size and long studies execute time, we will not be able to obtain reliable, high-quality clinical evidence about COVID-19 treatment in the near future. Improving the quality of study design, prioritizing promising drugs, and using different designs and statistical methods are worth advocating and recommending for the clinical trials of COVID-19 in China.","type":"Review","database":"MedRxiv","created":"2020-03-02"},{"id":83,"name":"Clinical findings in critical ill patients infected with SARS-Cov-2 in Guangdong Province, China: a multi-center, retrospective, observational study","author":"Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, Jianwei Li, Sibei Chen, Dongdong Liu, Zhimin Lin, Liang Zhou, Weiqun He, Xi","doi":"10.1101\/2020.03.03.20030668","abstract":"Abstract Background In December 2019, human infection with a novel coronavirus, known as SARS-CoV-2, was identified in Wuhan, China. The mortality of critical illness was high in Wuhan. Information about critically ill patients with SARS-CoV-2 infection outside of Wuhan is scarce. We aimed to provide the clinical features, treatment, and prognosis of the critically ill patients with SARS-CoV-2 infection in Guangdong Province. Methods In this multi-centered, retrospective, observational study, we enrolled critically ill patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) in Guangdong Province. Demographic data, symptoms, laboratory findings, comorbidities, treatments, and prognosis were collected. Data were compared between patients with and without intubation. Results Forty-five critically ill patients with SARS-CoV-2 pneumonia were identified in 7 ICUs in Guangdong Province. The mean age was 56.7 years, and 29 patients (64.4%) were men. The most common symptoms at the onset of illness were high fever and cough. Majority of patients presented with lymphopenia and elevated lactate dehydrogenase. Treatment with antiviral drugs was initiated in all the patients. Thirty-seven patients (82.2%) had developed acute respiratory distress syndrome, and 13 (28.9%) septic shock. A total of 20 (44.4%) patients required intubation and 9 (20%) required extracorporeal membrane oxygenation. As of February 28th 2020, only one patient (2.2%) had died and half of them had discharged of ICU. Conclusions Infection with SARS-CoV-2 in critical illness is characterized by fever, lymphopenia, acute respiratory failure and multiple organ dysfunction. Compared with critically ill patients infected with SARS-CoV-2 in Wuhan, the mortality of critically ill patients in Guangdong Province was relatively low. These data provide some general understandings and experience for the critical patients with SARS-CoV-2 outside of Wuhan.","type":"Research","database":"MedRxiv","created":"2020-03-05"},{"id":82,"name":"Appealing for Efficient, Well Organized Clinical Trials on COVID-19","author":"Yang Zhao, Yongyue Wei, Sipeng Shen, Mingzhi Zhang, Feng Chen","doi":"10.1101\/2020.03.05.20031476","abstract":"The rapid emergence of clinical trials on COVID-19 stimulated a wave of discussion in scientific community. We reviewed the characteristics of interventional trials from Chinese Clinical Trial Registration (ChiCTR) and ClinicalTrials.gov. A total of 171 COVID-19-related interventional trials were identified on Feb 22nd, 2020. These trials are classified into 4 categories based on treatment modalities, including chemical drugs, biological therapies, traditional Chinese medicine treatments and other therapies. Our analysis focused on the issues of stage, design, randomization, blinding, primary endpoints definition and sample size of these trials. We found some studies with potential defects including unreasonable design, inappropriate primary endpoint definition, insufficient sample size and ethical issue. Clinical trials on COVID-19 should be designed based on scientific rules, ethics and benefits for patients.","type":"Comment","database":"MedRxiv","created":"2020-03-06"},{"id":81,"name":"Outcome reporting from protocols of clinical trials of Coronavirus Disease 2019 (COVID-19): a review","author":"Ruijin Qiu, Xuxu Wei, Mengzhu Zhao, Changming Zhong, Chen Zhao, Jiayuan Hu, Min Li, Ya Huang, Songjie Han, Tianmai He, Jing Chen, Hongcai Shang","doi":"10.1101\/2020.03.04.20031401","abstract":"Objectives: To examine heterogeneity of outcomes in protocols of clinical trials of Coronavirus Disease 2019 (COVID-19) and to identify outcomes for prioritization in developing a core outcome set (COS) in this field. Design: This study is a review. Data sources: Databases of ICMJE-accepted clinical trial registry platform were searched on February 14, 2020. Eligibility Criteria: Randomized controlled trials (RCTs) and non-RCTs of COVID-19 were considered.Conditions of patients include common type, severe type or critical type. Interventions include traditional Chinese medicine (TCM) and Western medicine. We excluded trials that for discharged patients, psychological intervention and complications of COVID-19. Data extraction and synthesis: The general information and outcomes, outcome measurement instruments and measurement times were extracted. The results were analysed by descriptive analysis. Results: 19 registry platforms were searched. A total of 97 protocols were included from 160 protocols. For protocols of TCM clinical trials, 76 outcomes from 16 outcome domains were reported, and almost half (34\/76, 44.74%) of outcomes were reported only once; the most frequently reported outcome was time of SARS-CoV-2 RNA turns to negative. 27 (27\/76, 35.53%) outcomes were provided one or more outcome measurement instruments. 10 outcomes were provided one or more measurement time frame. For protocols of western medicine clinical trials, 126 outcomes from 17 outcome domains were reported; almost half (62\/126, 49.21%) of outcomes were reported only once; the most frequently reported outcome was proportion of patients with negative SARS-CoV-2. 27 outcomes were provided one or more outcome measurement instruments. 40 (40\/126, 31.75%) outcomes were provided one or more measurement time frame. Conclusion: Outcome reporting in protocols of clinical trials of COVID-19 is inconsistent. Thus, developing a core outcome set is necessary. Keywords: Outcomes; clinical trials, COVID-19; review.","type":"Review","database":"MedRxiv","created":"2020-03-07"},{"id":80,"name":"Exploring diseases\/traits and blood proteins causally related to expression of ACE2, the putative receptor of 2019-nCov: A Mendelian Randomization analysis","author":"Shitao Rao, Alexandria Lau, Hon-Cheong So","doi":"10.1101\/2020.03.04.20031237","abstract":"The novel coronavirus 2019-nCoV has caused major outbreaks in many parts of the world. A better understanding of the pathophysiology of COVID-19 is urgently needed. Clinically, it is important to identify who may be susceptible to infection and identify treatments for the disease. There is good evidence that ACE2 is a receptor for 2019-nCoV, and studies also suggested that high expression of ACE2 may increase susceptibility to infection. Here we conducted a phenome-wide Mendelian randomization (MR) study to prioritize diseases\/traits and blood proteins that may be causally linked to ACE2 expression in the lung. Expression data was based on GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR analysis, as these drugs could potentially alter ACE2 expression and may be clinically relevant. Notably, MR is much less vulnerable to confounding and reverse causality compared to observational studies. The most consistent finding was a tentative causal association between diabetes-related traits and increased ACE2 expression. Based on one of the largest GWAS on type II diabetes (T2DM) to date (N=898,130), we found that T2DM is causally linked to raised ACE2 expression (beta=0.1835, 95% CI 0.0853-0.2817; p=2.49E-4; GSMR method). Significant associations (at nominal level; p<0.05) was also observed across multiple datasets, with different analytic methods, and for both type I and II diabetes. Other diseases\/traits having nominal significant associations with increased ACE2 included inflammatory bowel disease, (ER+) breast and lung cancers, asthma, smoking and elevated ALT, among others. We also uncovered a number of plasma\/serum proteins potentially linked to altered ACE2 expression, and the top enriched pathways included cytokine-cytokine-receptor interaction, VEGF signaling, JAK-STAT signaling etc. We also explored drugs that target some of the top-ranked proteins in the MR analysis. In conclusion, the current MR analysis reveals diseases\/traits and blood proteins that may causally affect ACE2 expression, which in turn may influence susceptibility to the infection. The proteome-wide MR analysis may shed light on the molecular mechanisms underlying ACE2 expression, and may help guide drug repositioning in the future. Nevertheless, we stress that further studies are required to verify our findings due to various limitations and the exploratory nature of some analyses.","type":"Research","database":"MedRxiv","created":"2020-03-07"},{"id":79,"name":"Coronavirus in pregnancy and delivery: rapid review and expert consensus","author":"Edward Mullins, David Evans, Russell Viner, Patrick O'Brien, Eddie Morris","doi":"10.1101\/2020.03.06.20032144","abstract":"BACKGROUND Person to person spread of COIVD-19 in the UK has now been confirmed. There are limited case series reporting the impact on women affected by coronaviruses (CoV) during pregnancy. In women affected by SARS and MERS, the case fatality rate appeared higher in women affected in pregnancy compared with non-pregnant women. We conducted a rapid, review to guide management of women affected by COVID -19 during pregnancy and developed interim practice guidance with the RCOG and RCPCH to inform maternity and neonatal service planning METHODS Searches were conducted in PubMed and MedRxiv to identify primary case reports, case series, observational studies or randomised-controlled trial describing women affected by coronavirus in pregnancy and on neonates. Data was extracted from relevant papers and the review was drafted with representatives of the RCPCH and RCOG who also provided expert consensus on areas where data were lacking RESULTS From 9964 results on PubMed and 600 on MedRxiv, 18 relevant studies (case reports and case series) were identified. There was inconsistent reporting of maternal, perinatal and neonatal outcomes across case reports and series concerning COVID-19, SARS, MERS and other coronaviruses. From reports of 19 women to date affected by COVID-19 in pregnancy, delivering 20 babies, 3 (16%) were asymptomatic, 1 (5%) was admitted to ICU and no maternal deaths have been reported. Deliveries were 17 by caesarean section, 2 by vaginal delivery, 8 (42%) delivered pre-term. There was one neonatal death, in 15 babies who were tested there was no evidence of vertical transmission. CONCLUSIONS Morbidity and mortality from COVID-19 appears less marked than for SARS and MERS, acknowledging the limited number of cases reported to date. Pre-term delivery affected 42% of women hospitalised with COVID-19, which may put considerable pressure on neonatal services if the UK reasonable worse-case scenario of 80% of the population affected is realised. There has been no evidence of vertical transmission to date. The RCOG and RCPCH have provided interim guidance to help maternity and neonatal services plan their response to COVID-19.","type":"Review","database":"MedRxiv","created":"2020-03-07"},{"id":78,"name":"Clinical Characteristics of Two Human to Human Transmitted Coronaviruses: Corona Virus Disease 2019 versus Middle East Respiratory Syndrome Coronavirus.","author":"Ping Xu, Guo-Dong Sun, Zhi-Zhong Li","doi":"10.1101\/2020.03.08.20032821","abstract":"After the outbreak of the middle east respiratory syndrome (MERS) worldwide in 2012. Currently, a novel human coronavirus has caused a major disease outbreak, and named corona virus disease 2019 (COVID-19). The emergency of MRES-COV and COVID-19 has caused global panic and threatened health security. Unfortunately, the similarities and differences between the two coronavirus diseases remain to be unknown. The aim of this study, therefore, is to perform a systematic review to compare epidemiological, clinical and laboratory features of COVID-19 and MERS-COV population. We searched PubMed, EMBASE and Cochrane Register of Controlled Trials database to identify potential studies reported COVID-19 or MERS-COV. Epidemiological, clinical and laboratory outcomes, the admission rate of intensive cure unit (ICU), discharge rate and fatality rate were evaluated using GraphPad Prism software. Thirty-two studies involving 3770 patients (COVID-19 = 1062, MERS-COV = 2708) were included in this study. The present study revealed that compared with COVID-19 population, MERS-COV population had a higher rate of ICU admission, discharge and fatality and longer incubation time. It pointed out that fever, cough and generalised weakness and myalgia were main clinical manifestations of both COVID-19 and MERS-COV, whereas ARDS was main complication. The most effective drug for MERS-COV is ribavirin and interferon.","type":"Research","database":"MedRxiv","created":"2020-03-09"},{"id":77,"name":"Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19","author":"JIan Chen, Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, WenHu Yu, Liping Zhu, Shaohui Cheng, Xiaogen Tao, Huan Zhang","doi":"10.1101\/2020.03.09.20033068","abstract":"Background The illness progress of partial patient of COVID-19 is rapid and the mortality rate is high.we aim to describe the clinical features in death cases with COVID-19. Methods In this single center, observational study, We recruited all Death Cases with COVID-19 from Dec 30, 2019 to Feb 16, 2020 in Intensive care unit of Wuhan Jinyintan Hospital.Demographics, basic diseases, X-ray\/CT results, possible therapy strategies and test results when their entrance into admission, ICU and 48 h before death were collected and analyzed. Results This study involved 101 COVID-19 dead cases in Intensive care unit of Wuhan Jinyintan Hospital.47 patients went directly to the ICU because of critical condition, and 54 patients were transferred to ICU with aggravated condition.57 (56.44%) were laboratory confirmed by RT-PCR, and 44 (43.6%) were consistent with clinical diagnostic criteria.The cases included 64 males and 37 females with average age of 65.46 years (SD 9.74). The blood type distribution was significantly different, with type A 44.44%, type B 29.29%, type AB 8.08% and type O 18.19%.The clinical manifestations of new coronavirus pneumonia are non-specific,the common symptom was fever (91 [90.10%] of 101 patients),Cough (69[68.32%]) and dyspnea (75[74.26%]). Neutrophils, PCT, CRP,IL-6,D-dimer gradually increased as time went on.Myocardial enzymes were abnormal in most patients at admission,with the progress of the disease, myocardial damage indicators were significantly increased.61(60.40%) used antiviral drugs,59(58.42%) used glucocorticoids, 63.37% used intravenous immunoglobulins, and 44.55% used thymosin preparations. All patients received antibiotic treatment, 63(62.38%) used restricted antibiotics, 23(22.78%) used antifungal drugs.84(83.17%) used non-invasive ventilator or high-flow oxygen therapy equipment, and 76.24% used invasive mechanical ventilation. 7 patients were treated with ECMO and 8 patients were treated with CRRT.The median time from ARDS to invasive mechanical ventilation was 3.00 days(IQR 0.00-6.00). The duration of invasive mechanical ventilation was 5 days (IQR2.00-8.00). Conclusions Critical COVID-19 can cause fatal respiratory distress syndrome and multiple organ failure with high mortality rate. Heart may be the earliest damaged organ except the lungs. Secondary infection in the later period is worthy of attention.","type":"Research","database":"MedRxiv","created":"2020-03-11"},{"id":76,"name":"Protocol of a randomized controlled trial testing inhaled Nitric Oxide in mechanically ventilated patients with severe acute respiratory syndrome in COVID-19 (SARS-CoV-2).","author":"Chong Lei, Binxiao Su, Hailong Dong, Andrea Bellavia, Raffaele Di Fenza, Bijan Safaee Fakhr, Stefano Gianni, Luigi Giuseppe Grassi, Robert Kacmarek, Caio Cesar Araujo Morais, Riccardo Pinciroli, Emanu","doi":"10.1101\/2020.03.09.20033530","abstract":"Introduction. Severe acute respiratory syndrome (SARS-CoV-2) due to novel Coronavirus (2019-nCoV) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for 2019-nCoV. Nitric oxide is a selective pulmonary vasodilator gas used as a rescue therapy in refractory hypoxemia due to acute respiratory distress syndrome (ARDS). In has also shown in-vitro and clinical evidence that inhaled nitric oxide gas (iNO) has antiviral activity against other strains of coronavirus. The primary aim of this study is to determine whether inhaled NO improves oxygenation in patients with hypoxic SARS-CoV2. This is a multicenter randomized controlled trial with 1:1 individual allocation. Patients will be blinded to the treatment. Methods and analysis. Intubated patients admitted to the intensive care unit with confirmed SARS-CoV-2 infection and severe hypoxemia will be randomized to receive inhalation of NO (treatment group) or not (control group). Treatment will be stopped when patients are free from hypoxemia for more than 24 hours. The primary outcome evaluates levels of oxygenation between the two groups at 48 hours. Secondary outcomes include rate of survival rate at 28 and 90 days in the two groups, time to resolution of severe hypoxemia, time to achieve negativity of SARS-CoV-2 RT-PCR tests. Ethics and dissemination. The study protocol has been approved by the Investigational Review Board of Xijing Hospital (Xian, China) and pending the Partners Human Research Committee (Boston, USA). Recruitment will start after approval of both IRBs and local IRBs at other enrolling centers. Results of this study will be published in scientific journals, presented at scientific meetings, reported through flyers and posters, and published on related website or media in combating against this widespread contagious diseases. Trial registration. Clinicaltrials.gov. NCT submitted","type":"Other","database":"MedRxiv","created":"2020-03-12"},{"id":75,"name":"Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19","author":"Lorenzo Berra, Chong Lei, Binxiao Su, Hailong Dong, Bijan Safaee Fakhr, Luigi Giuseppe Grassi, Raffaele Di Fenza, Stefano Gianni, Riccardo Pinciroli, Emanuele Vassena, Caio Cesar Araujo Morais, Andrea","doi":"10.1101\/2020.03.10.20033522","abstract":"Introduction: the current worldwide outbreak of Coronavirus disease 2019 (COVID-19) due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-mediated acute respiratory syndrome, and this can be related to its viricidal effect. The time from the symptoms onset to the development of severe respiratory distress is relatively long. We hypothesize that high concentrations of inhaled NO administered during early phases of COVID-19 infection can prevent the progression of the disease. Methods and analysis: This is a multicenter randomized controlled trial. Spontaneous breathing patients admitted to the hospital for symptomatic COVID-19 infection will be eligible to enter the study. Patients in the treatment group will receive inhaled NO at high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days in addition to the hospital care. Patient in the control group will receive only hospital care. The primary outcome is the percentage of patients requiring endotracheal intubation due to the progression of the disease in the first 28 days from enrollment in the study. Secondary outcomes include mortality at 28 days, proportion of negative test for SARS-CoV-2 at 7 days and time to clinical recovery. Ethics and dissemination: The trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xi an, China) and The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment is expected to start in March 2020. Results of this study will be published in scientific journals, presented at scientific meetings, and on related website or media in fighting this widespread contagious disease. Trial registration. Clinicaltrials.gov. NCT submitted","type":"Other","database":"MedRxiv","created":"2020-03-12"},{"id":73,"name":"A high efficient hospital emergency responsive mode is the key of successful treatment of 100 COVID-19 patients in Zhuhai","author":"Jin Huang, Zhonghe Li, Xiujuan Qu, Xiaobin Zheng, Changli Tu, Meizhu Chen, Cuiyan Tan, Jing Liu, Hong Shan","doi":"10.1101\/2020.03.15.20034629","abstract":"Background: Since December 2019, Coronavirus Disease 2019 (COVID-19) emerged in Wuhan city and rapidly spread throughout China. The mortality of novel coronavirus pneumonia (NCP) in severe and critical cases is very high. Facing this kind of public health emergency, high efficient administrative emergency responsive mode in designated hospital is needed. Method: As an affiliated hospital of Sun Yat-sen University, our hospital is the only designated one for diagnosis and treatment of COVID-19 in Zhuhai, a medium-sized city. Novel coronavirus pneumonia department, which is administrative led by the president of hospital directly, has been established at early stage of epidemic crisis in my hospital. In NCP department, there are core members of Pulmonary and Critical Care Medicine (PCCM) specialist and multidisciplinary team. Don't stick to national guidelines of NCP, based on professional opinion by respiratory professor and expert group, we focused on individualized treatment and timely adjustment of treatment and management strategies in working about COVID-19 patients. Results: 1. High working efficiency: By Mar 02, 2020, we have completed 2974 citywide consultations and treatment of 366 inpatients, including 101 patients diagnosed with COVID-19. 2. Excellent therapeutic effectAmong 101 hospitalized patients with confirmed COVID-19, all were cured and discharged, except for one death. No secondary hospital infection, no pipeline infection and no pressure sore were found in all patients. 3. Finding and confirming person-to-person transmission characteristic of COVID-19 prior to official release conference: Strengthened protection is key point to zero infection in healthcare group and medical faculty and lower rate of second generation infectious patients. 4. Timely adjustment management and treatment strategy prior to guideline update: The first evidence of digestive tract involvement in COVID-19 has been found, and the earliest clinical trial of chloroquine in the treatment of COVID-19 has been carried out in our hospital. Conclusions: In our hospital, establishment of NCP department, which is administratively led by the president of hospital directly and specialized conduct by respiratory professor, is the key to success in management and treatment of COVID-19 patients. This hospital emergency responsive mode could provide reference for other hospitals and cities in epidemic situation.","type":"Comment","database":"MedRxiv","created":"2020-03-16"},{"id":72,"name":"A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19","author":"Drifa Belhadi, Nathan Peiffer-Smadja, Fran\u00e7ois-Xavier Lescure, Yazdan Yazdanpanah, France Mentr\u00e9, C\u00e9dric Laou\u00e9nan","doi":"10.1101\/2020.03.18.20038190","abstract":"Background: Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials. Methods: A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms \"2019-nCoV\", \"COVID-19\", \"SARS-CoV-2\", \"Hcov-19\", \"new coronavirus\", \"novel coronavirus\". We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents. Findings: Out of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir\/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir\/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%). Interpretation: Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking. Funding: None","type":"Review","database":"MedRxiv","created":"2020-03-19"},{"id":71,"name":"Estimating the Risks from COVID-19 Infection in Adult Chemotherapy Patients","author":"Matt Williams, Kerlann Le Calvez, Ella Mi, Jiarong Chen, Seema Dadhania, Lillie Pakzad-Shahabi","doi":"10.1101\/2020.03.18.20038067","abstract":"The SARS-CoV-2 (COVID-19) novel coronavirus represents a significant health risk, particularly in older patients. Cancer is one of the leading causes of death in most rich countries, and delivering chemotherapy may be associated with increased risk in the presence of a pandemic infection. Estimating this risk is crucial in making decisions about balancing risks and benefits from administering chemotherapy. However, there are no specific data about chemotherapy risks per se. Here we develop a simple model to estimate the potential harms in patients undergoing chemotherapy during a COVID outbreak. We use age-related case fatality rates as a basis for estimating risk, and use previous data from risk of death during influenza outbreaks to estimate the additional risk associated with chemotherapy. We use data from randomised trials to estimate benefit across a range of curative and palliative settings, and address the balance of benefit against the risk of harm. We then use those data to estimate the impact on national chemotherapy delivery patterns.","type":"Research","database":"MedRxiv","created":"2020-03-19"},{"id":70,"name":"A prospect on the use of antiviral drugs to control local outbreaks of COVID-19","author":"Andrea Torneri, Pieter Jules Karel Libin, Joris Vanderlocht, Anne-Mieke Vandamme, Johan Neyts, Niel Hens","doi":"10.1101\/2020.03.19.20038182","abstract":"Background: Current outbreaks of COVID-19 are threatening the health care systems of several countries around the world. Control measures, based on isolation and quarantine, have been shown to decrease and delay the burden of the ongoing epidemic. With respect to the ongoing COVID-19 epidemic, recent modelling work shows that this intervention technique may be inadequate to control local outbreaks, even when perfect isolation is assumed. Furthermore, the effect of infectiousness prior to symptom onset combined with a significant proportion of asymptomatic infectees further complicates the use of contact tracing. Antivirals, which decrease the viral load and reduce the infectiousness, could be integrated in the control measures in order to augment the feasibility of controlling the epidemic. Methods: Using a simulation-based model of viral transmission we tested the efficacy of different intervention measures for the control of COVID-19. For individuals that were identified through contact tracing, we evaluate two procedures: monitoring individuals for symptoms onset and testing of individuals. Moreover, we investigate the effect of a potent antiviral compound on the contact tracing process. Findings: The use of an antiviral drug, in combination with contact tracing, quarantine and isolation, results in a significant decrease of the final size, the peak incidence, and increases the probability that the outbreak will fade out. Interpretation: For an infectious disease in which presymptomatic infections are plausible, an intervention measure based on contact tracing performs better when realized together with testing instead of monitoring, provided that the test is able to detect infections during the incubation period. In addition, in all tested scenarios, the model highlights the benefits of the administration of an antiviral drug in addition to quarantine, isolation and contact tracing. The resulting control measure, could be an effective strategy to control local and re-emerging outbreaks of COVID-19.","type":"Research","database":"MedRxiv","created":"2020-03-19"},{"id":68,"name":"Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial","author":"Chang Chen, Jianying Huang, Ping Yin, Yi Zhang, Zhenshun Cheng, Jianyuan Wu, Song Chen, Yongxi Zhang, Bo Chen, Mengxin Lu, Yongwen Luo, Jingyi Zhang, Xinghuan Wang","doi":"10.1101\/2020.03.17.20037432","abstract":"Importance: WHO has made the assessment that coronavirus disease 2019 (COVID-19) can be characterized as a pandemic. So far, there is no clinically proven effective antiviral drug for COVID-19. Objective: To compare the efficacy and safety of favipiravir and arbidol to treat COVID-19 patients on clinical recovery rate of day 7. Design: Prospective, multicenter, open-label, randomized superiority trial in February, 2020. Setting: Multicenter study. Participants: Patients with confirmed COVID-19 admitted to 3 hospitals from Feb. 20, 2020 to Mar. 12, 2020. Interventions: Conventional therapy + favipiravir or arbidol. Main Outcomes and Measures: The primary outcome was clinical recovery rate of day 7. Duration of fever, cough relief time and auxiliary oxygen therapy or noninvasive mechanical ventilation rate were the secondary outcomes. The patients with chest CT imaging and laboratory-confirmed COVID-19 infection, aged 18 years or older were randomly assigned to receive favipiravir or arbidol. Safety data were collected for further follow-up for a week. Results: 120 patients were assigned to favipiravir group (116 assessed) and 120 to arbidol group (120 assessed). In full analysis set (FAS) cohort, for moderate patients with COVID-19, clinical recovery rate of day 7 was 55.86% in the arbidol group and 71.43% in the favipiravir group (P=0.0199). For moderate COVID-19 patients and COVID-19 patients with hypertension and\/or diabetes, the latency to fever reduction and cough relief in favipiravir group was significantly shorter than that in arbidol group (both P<0.001), but there was no statistical difference was observed of auxiliary oxygen therapy or noninvasive mechanical ventilation rate (both P>0.05). The most frequently observed treatment-associated adverse events were abnormal LFT, psychiatric symptom reactions, digestive tract reactions and raised serum uric acid (3 [2.50%] in arbidol group vs 16 [13.79%] in favipiravir group, P<0.0001). Conclusions and Relevance: In moderate COVID-19 patients untreated with antiviral previously, favipiravir can be considered as a preferred treatment compared to arbidol because of superior clinical recovery rate of day 7 and more effectively reduced incidence of fever, cough besides some manageable antiviral-associated adverse effects. Trial Registration: This study is registered with Chictr.org.cn, number ChiCTR2000030254.","type":"Research","database":"MedRxiv","created":"2020-03-19"},{"id":67,"name":"The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study","author":"Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, Cheng Peng, Mingchao Yuan, Jinyan Huang, Zejun Wang, Jianhong Yu, Xiaoxiao Gao, Dan Wang, ","doi":"10.1101\/2020.03.16.20036145","abstract":"Currently, there are no approved specific antiviral agents for 2019 novel coronavirus disease (COVID-19). In this study, ten severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 days after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 days. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 days. Several parameters tended to improve as compared to pre-transfusion, including increased lymphocyte counts (0.65*109\/L vs. 0.76*109\/L) and decreased C-reactive protein (55.98 mg\/L vs. 18.13 mg\/L). Radiological examinations showed varying degrees of absorption of lung lesionswithin 7 days. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was welltolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.","type":"Research","database":"MedRxiv","created":"2020-03-22"},{"id":66,"name":"Climatic influences on the worldwide spread of SARS-CoV-2","author":"Michail Bariotakis, George Sourvinos, Elias Castanas, Stergios A Pirintsos","doi":"10.1101\/2020.03.19.20038158","abstract":"The rapid global spread of the novel, pathogenic, SARS-CoV-2 causing the severe acute respiratory disease COVID-19, becomes a major health problem worldwide and pose the need for international predictive programs. Given the lack of both specific drugs and an efficient preventive vaccine, the expectation that the SARS-CoV-2 transmission rate might decrease in temperate regions during summer, dominated in the social scene. Here, we attempted a prediction of the worldwide spread of the infections based on climatic data, expressed by bioclimatic variables. The calculated probability maps shown that potential areas of infection follow a shift from the Tropical to Temperate and Mediterranean Bioclimatic regions. Maps show an increased probability of infections in Europe, followed by an expansion covering areas of the Middle East and Northern Africa, as well as Eastern coastal areas of North America, South-Eastern coastal areas of Latin America and two areas of Southern Australia. Our approach may, therefore, be of value for the incorporation of climatic influences in the design and implementation of public health policies. Maps are available (constantly updated) at https:\/\/navaak.shinyapps.io\/CVRisk\/.","type":"Research","database":"MedRxiv","created":"2020-03-22"},{"id":65,"name":"Effectiveness and safety of antiviral or antibody treatments for coronavirus","author":"Patricia Rios, Amruta Radhakrishnan, Jesmin Antony, Sonia M. Thomas, Mathew Muller, Sharon E. Straus, Andrea C. Tricco","doi":"10.1101\/2020.03.19.20039008","abstract":"Background: To identify safe and effective medical countermeasures (e.g., antivirals\/antibodies) to address the current outbreak of a novel coronavirus (COVID-19) Methods: Comprehensive literature searches were developed by an experienced librarian for MEDLINE, EMBASE, the Cochrane Library, and biorxiv.org\/medrxiv.org; additional searches for ongoing trials and unpublished studies were conducted in clinicaltrials.gov and the Global Infectious Diseases and Epidemiology Network (GIDEON). Title\/abstract and full-text screening, data abstraction, and risk of bias appraisal were carried out by single reviewers. Results: 54 studies were included in the review: three controlled trials, 10 cohort studies, seven retrospective medical record\/database studies, and 34 case reports or series. These studies included patients with severe acute respiratory syndrome (SARs, n=33), middle east respiratory syndrome (MERS, n=16), COVID-19 (n=3), and unspecified coronavirus (n=2). The most common treatment was ribavirin (n=41), followed by oseltamivir (n=10) and the combination of lopinavir\/ritonavir (n=7). Additional therapies included broad spectrum antibiotics (n=30), steroids (n=39) or various interferons (n=12). No eligible studies examining monoclonal antibodies for COVID-19 were identified. One trial found that ribavirin prophylactic treatment statistically significantly reduced risk of MERS infection in people who had been exposed to the virus. Of the 21 studies reporting rates of ICU admission in hospitalized SARS or MERS patients, none reported statistically significant results in favour of or against antiviral therapies. Of the 40 studies reporting mortality rates in hospitalized SARS or MERS patients, one cohort study (MERS) and one retrospective study (SARS) found a statistically significant increase in the mortality rate for patients treated with ribavirin. Eighteen studies reported potential drug-related adverse effects including gastrointestinal symptoms, anemia, and altered liver function in patients receiving ribavirin. Conclusion: The current evidence for the effectiveness and safety of antiviral therapies for coronavirus is inconclusive and suffers from a lack of well-designed prospective trials or observational studies, preventing any treatment recommendations from being made. However, it is clear that the existing body of evidence is weighted heavily towards ribavirin (41\/54 studies), which has not shown conclusive evidence of effectiveness and may cause harmful adverse events so future investigations may consider focusing on other candidates for antiviral therapy.","type":"Research","database":"MedRxiv","created":"2020-03-22"},{"id":64,"name":"Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial","author":"Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, Rong-Hua Xie, Bin Wang, Xiu-Xuan Sun, Xiang-Min Yang, Peng Lin, Jie-Jie G","doi":"10.1101\/2020.03.21.20040691","abstract":"Background: SARS-CoV-2 is a novel human coronavirus, there is no specific antiviral drugs. It has been proved that host-cell-expressed CD147 could bind spike protein of SARS-CoV-2 and involve in host cell invasion. Antibody against CD147 could block the infection of SARS-CoV-2. We aimed to assess the efficacy and safety of meplazumab, a humanized anti-CD147 antibody, as add-on therapy in patients with COVID-19 pneumonia. Methods: All patients received recommended strategy from Diagnosis and Treatment for 2019 Novel Coronavirus Diseases released by National Health Commission of China. Eligible patients were add-on administered 10 mg meplazumab intravenously at days 1, 2, and 5. Patients hospitalized in the same period were observed as concurrent control. The endpoints include virological clearance rate, case severity, chest radiographic, and laboratory test. This trial was approved by the Ethics Committee of Institution at the Tangdu hospital, and registered with ClinicalTrials.gov, NCT 04275245. Findings:17 patients were enrolled and assigned to meplazumab group between Feb 3, 2020 and Feb 10, 2020. 11 hospitalized patients served as concurrent control. Baseline characteristics were generally balanced across two groups. Compared to control group, meplazumab treatment significantly improved the discharged (p=0.006) and case severity (p=0.021) in critical and severe patients. The time to virus negative in meplazumab group was reduced than that in control group (median 3, 95%CI[1.5-4.5] vs. 13, [6.5-19.5]; p=0.014, HR=0.37, 95%CI[0.155-0.833]). The percentages of patients recovered to the normal lymphocyte count and CRP concentration were also increased remarkably and rapidly in meplazumab group. No adverse effect was found in meplazumab-treated patients. Interpretation:Meplazumab efficiently improved the recovery of patients with SARS-CoV-2 pneumonia with a favorable safety profile. Our results support to carry out a large-scale investigation of meplazumab as a treatment for COVID-19 pneumonia. Funding:National Science and Technology Major Project.","type":"Research","database":"MedRxiv","created":"2020-03-23"},{"id":63,"name":"First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients","author":"Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J","doi":"10.1101\/2020.03.22.20034041","abstract":"As coronavirus disease 2019 (COVID-19) outbreak, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), started in China in January, 2020, repurposing approved drugs is emerging as important therapeutic options. We reported here the first clinical study using hepatitis C virus (HCV) protease inhibitor, danoprevir, to treat COVID-19 patients. Danoprevir (Ganovo) is a potent HCV protease (NS3\/4A) inhibitor (IC50 = 0.29 nM), which was approved and marketed in China since 2018 to treat chronic hepatitis C patients. Ritonavir is a CYP3A4 inhibitor to enhance plasma concentration of danoprevir while it also acts as a human immunodeficiency virus (HIV) protease inhibitor at high doses. The chymotrypsin-like protease of SARS-CoV-2 shares structure similarity with HCV and HIV proteases. In the current clinical study (NCT04291729) conducted at the Nineth Hospital of Nanchang, we evaluated therapeutic effects of danoprevir, boosted by ritonavir, on treatment naive and experienced COVID-19 patients. The data from this small-sample clinical study showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all eleven patients enrolled, two naive and nine experienced, were discharged from the hospital as they met all four conditions as follows: (1) normal body temperature for at least 3 days; (2) significantly improved respiratory symptoms; (3) lung imaging shows obvious absorption and recovery of acute exudative lesion; and (4) two consecutive RT-PCR negative tests of SARS-CoV-2 nucleotide acid (respiratory track sampling with interval at least one day). Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.","type":"Research","database":"MedRxiv","created":"2020-03-23"},{"id":62,"name":"Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients","author":"Yingxia Liu, Fengming Huang, Jun Xu, Penghui Yang, Yuhao Qin, Mengli Cao, Zhaoqin Wang, Xiaohe Li, Shaogeng Zhang, Lu Ye, Jingjun Lv, Jie Wei, Tuxiu Xie, Hong Gao, Kai-Feng Xu, Fusheng Wang, Lei Liu, ","doi":"10.1101\/2020.03.20.20039586","abstract":"Summary Background The novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak started at the end of 2019 in Wuhan, China, and spread over 100 countries. SARS-CoV-2 uses the membrane protein Angiotensin I converting enzyme 2(ACE2) as a cell entry receptor. Indeed, it was reported that the balance of Renin-Angiotensin System (RAS), regulated by both ACE and ACE2, was altered in COVID-19 patients. It is controversial, however, whether commonly used anti-hypertensive drugs Angiotensin I converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB) shall be continued in the confirmed COVID-19 patients. This study was designed to investigate any difference in disease severity between COVID-19 patients with hypertension comorbidity. The included COVID-19 patients used ACEI, ARB, calcium channel blockers (CCB), beta blockers (BB), or thiazide to treat preexisting hypertension prior to the hospital were compared to patients who did not take any of those drugs. Methods In this multicentre retrospective study, clinical data of 511 COVID-19 patients were analyzed. Patients were categorized into six sub-groups of hypertension comorbidity based on treatment using one of anti-hypertension drugs (ACEI, ARB, CCB, BB, thiazide), or none. A meta-analysis was performed to evaluate the use of ACEI and ARB associated with pneumonia using published studies. Findings Among the elderly (age>65) COVID-19 patients with hypertension comorbidity, the risk of COVID-19-S (severe disease) was significantly decreased in patients who took ARB drugs prior to hospitalization compared to patients who took no drugs (OR=0.343, 95% CI 0.128-0.916, p=0.025). The meta-analysis showed that ARB use has positive effects associated with morbidity and mortality of pneumonia. Interpretation Elderly (age>65) COVID-19 patients with hypertension comorbidity who are taking ARB anti-hypertension drugs may be less likely to develop severe lung disease compared to patients who take no anti-hypertension drugs. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences","type":"Research","database":"MedRxiv","created":"2020-03-26"},{"id":61,"name":"Core Outcome Set for Traditional Chinese and Western Medicine Clinical Trials of COVID-19","author":"Ruijin Qiu, Chen Zhao, Tengxiao Liang, Xuezeng Hao, Ya Huang, Xiaoyu Zhang, Zhao Chen, Xuxu Wei, Mengzhu Zhao, Changming Zhong, Jiayuan Hu, Min Li, Songjie Han, Tianmai He, Jing Chen, Hongcai Shang","doi":"10.1101\/2020.03.23.20041533","abstract":"Background: There are a large number of clinical trials for COVID-19. But the heterogeneity of outcomes may result in some clinical trials cannot be compared or merged. It is emergency to develop a core outcome set (COS) for clinical trials. Methods: A preliminary list of outcomes were developed after a systematic review of protocols of clinical trials for COVID-19. Then two rounds of Delphi survey was conducted. The stakeholders included traditional Chinese medicine (TCM) experts, Western medicine experts, nurses and the public. Patients with confirmed COVID-19 were also invited to participate in a questionnaire with simple language. Frontline clinicians (including TCM and Western medicine clinicians), nurse, methodologist, evidence-based medicine researcher and staff from Chinese Clinical Trials Registry participate in video conference to vote. Results: 97 eligible study protocols were identified from 160 clinical trials. 76 outcomes were identified from TCM clinical trials, 126 outcomes were identified from Western medicine clinical trials. In the end, 145 were included in the first round of Delphi survey. In the end, a COS was developed for clinical trials of TCM and Western medicine was developed. The COS includes Clinical outcome (recovery\/ improvement\/ progression\/ death), etiology (SARS-CoV-2 nucleic acid tests, viral load), inflammatory factor (CRP), vital signs (temperature, respiration), blood and lymphatic system outcomes (lymphocyte, virus antibody), respiratory outcomes (chest imaging, blood oxygen saturation, PaO2\/FiO2, arterial blood gas analysis, mechanical ventilation, oxygen intake, pneumonia severity index), clinical efficacy (rate of preventing mild to moderate type patients from progressing to severe type), symptoms (clinical symptom score). The outcomes were recommended according to different types of disease. Outcome measurement instrument\/definition were also recommended. Conclusion: A COS for COVID-19 may improve consistency of outcome reporting in clinical trials, which may help identify valued interventions after comparing different trials when the researchers report the same outcomes.","type":"Review","database":"MedRxiv","created":"2020-03-26"},{"id":60,"name":"A Simple Mathematical Model for Estimating the Inflection Points of COVID-19 Outbreaks","author":"Zhanshan (Sam) Ma","doi":"10.1101\/2020.03.25.20043893","abstract":"Background: Exponential-like infection growths leading to peaks (which could be the inflection points or turning points) are usually the hallmarks of infectious disease outbreaks including coronaviruses. To predict the inflection points, i.e., inflection time (Tmax) & maximal infection number (Imax) of the novel coronavirus (COVID-19), we adopted a trial and error strategy and explored a series of approaches from simple logistic modeling (that has an asymptomatic line) to sophisticated tipping point detection techniques for detecting phase transitions but failed to obtain satisfactory results. Method: Inspired by its success in diversity-time relationship (DTR), we apply the PLEC (power law with exponential cutoff) model for detecting the inflection points of COVID-19 outbreaks. The model was previously used to extend the classic species-time relationship (STR) for general DTR (Ma 2018), and it has two secondary parameters (computed from its 3 parameters including power law scaling parameter w, taper-off parameter d to overwhelm virtually exponential growth ultimately, and a parameter c related to initial infections): one that was originally used for estimating the potential or dark biodiversity is proposed to estimate the maximal infection number (Imax) and another is proposed to determine the corresponding inflection time point (Tmax). Results: We successfully estimated the inflection points [Imax, Tmax] for most provinces ({approx} 85%) in China with error rates <5% in both Imax and Tmax. We also discussed the constraints and limitations of the proposed approach, including (i) sensitive to disruptive jumps, (ii) requiring sufficiently long datasets, and (iii) limited to unimodal outbreaks.","type":"Research","database":"MedRxiv","created":"2020-03-26"},{"id":59,"name":"Therapeutic Application of Chloroquine in Clinical Trials for COVID-19","author":"Divya RSJB Rana, Santosh Dulal","doi":"10.1101\/2020.03.22.20040964","abstract":"The novel corona virus disease -2019 (COVID-19) pandemic has caused a massive global public health havoc. Recent clinical trials carried out in China has found a promising therapeutic application of chloroquine and hydroxychloroquine for COVID-19. This study meticulously evaluated the various dosages of chloroquine and hydroxychloroquine utilized in clinical trials registered in Chinese and US clinical trial registries for the treatment of pneumonia caused by SARS-CoV-2.","type":"Other","database":"MedRxiv","created":"2020-03-26"},{"id":58,"name":"Quantifying treatment effects of hydroxychloroquine and azithromycin for COVID-19: a secondary analysis of an open label non-randomized clinical trial","author":"Andrew A. Lover","doi":"10.1101\/2020.03.22.20040949","abstract":"Human infections with a novel coronavirus (SARS-CoV-2) were first identified via syndromic surveillance in December of 2019 in Wuhan China. Since identification, infections (coronavirus disease-2019; COVID-19) caused by this novel pathogen have spread globally, with more than 250,000 confirmed cases as of March 21, 2020. An open-label clinical trial has just concluded, suggesting improved resolution of viremia with use of two existing therapies: hydroxychloroquine (HCQ) as monotherapy, and in combination with azithromycin (HCQ-AZ). The results of this important trial have major implications for global policy in the rapid scale-up and response to this pandemic. The authors present results with p-values for differences in proportions between the study arms, but their analysis is not able to provide effect size estimates. To address this gap, more modern analytical methods including survival models, have been applied to these data, and show modest to no impact of HCQ treatment, with more significant effects from the HCQ-AZ combination, potentially suggesting a role for co-infections in COVID-19 pathogenesis. The trial of Gautret and colleagues, with consideration of the effect sizes, and p-values from multiple models, does not provide sufficient evidence to support wide-scale rollout of HCQ monotherapy for the treatment of COVID-19; larger randomzied studies should be considered. However, these data do suggest further study of HCQ-AZ combination therapy should be prioritized as rapidly as possible.","type":"Research","database":"MedRxiv","created":"2020-03-26"},{"id":57,"name":"Modelling SARS-CoV-2 Dynamics: Implications for Therapy","author":"Kwang Su Kim, VKeisuke Ejima, Yusuke Ito, Shoya Iwanami, Hirofumi Ohashi, Yoshiki Koizumi, Yusuke Asai, Shinji Nakaoka, Koichi Watashi, Robin N Thompson, Shingo Iwami","doi":"10.1101\/2020.03.23.20040493","abstract":"The scientific community is focussed on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data collected from the same specimen (throat \/ nasal swabs or nasopharyngeal \/ sputum \/ tracheal aspirate), we compare within-host dynamics for patients infected in the current outbreak with analogous dynamics for MERS-CoV and SARS-CoV infections. Our quantitative analyses revealed that SARS-CoV-2 infection dynamics are more severe than those for mild cases of MERS-CoV, but are similar to severe cases, and that the viral dynamics of SARS-CoV infection are similar to those of MERS-CoV in mild cases but not in severe case. Consequently, SARS-CoV-2 generates infection dynamics that are more severe than SARS-CoV. Furthermore, we used our viral dynamics model to predict the effectiveness of unlicensed drugs that have different methods of action. The effectiveness was measured by AUC of viral load. Our results indicated that therapies that block de novo infections or virus production are most likely to be effective if initiated before the peak viral load (which occurs around three days after symptom onset on average), but therapies that promote cytotoxicity are likely to have only limited effects. Our unique mathematical approach provides insights into the pathogenesis of SARS-CoV-2 in humans, which are useful for development of antiviral therapies.","type":"Research","database":"MedRxiv","created":"2020-03-26"},{"id":56,"name":"Genetic Profiles in Pharmacogenes Indicate Personalized Drug Therapy for COVID-19","author":"Lei-Yun Wang, Jia-Jia Cui, Qian-Ying OuYang, Yan Zhan, Yi-Min Wang, Xiang-Yang Xu, Cheng-Xian Guo, JiYe Yin","doi":"10.1101\/2020.03.23.20041350","abstract":"Background: The coronavirus disease 2019 (COVID-19) has become a global pandemic currently. Many drugs showed potential for COVID-19 therapy. However, genetic factors which can lead to different drug efficiency and toxicity among populations are still undisclosed in COVID-19 therapy. Methods: We selected 67 potential drugs for COVID-19 therapy (DCTs) from clinical guideline and clinical trials databases. 313 pharmaco-genes related to these therapeutic drugs were included. Variation information in 125,748 exomes were collected for racial differences analyses. The expression level of pharmaco-genes in single cell resolution was evaluated from single-cell RNA sequencing (scRNA-seq) data of 17 healthy adults. Results: Pharmacogenes, including CYP3A4, ABCB1, SLCO1B1, ALB, CYP3A5, were involved in the process of more than multi DCTs. 224 potential drug-drug interactions (DDI) of DCTs were predicted, while 112 of them have been reported. Racial discrepancy of common nonsynonymous mutations was found in pharmacogenes including: VDR, ITPA, G6PD, CYP3A4 and ABCB1 which related to DCTs including ribavirin, -interferon, chloroquine and lopinavir. Moreover, ACE2, the target of 2019-nCoV, was only found in parts of lung cells, which makes drugs like chloroquine that prevent virus binding to ACE2 more specific than other targeted drugs such as camostat mesylate. Conclusions: At least 17 drugs for COVID-19 therapy with predictable pharmacogenes should be carefully utilized in risk races which are consisted of more risk allele carriers. At least 29 drugs with potential of DDIs are reported to be affected by other DDIs, they should be replaced by similar drugs without interaction if it is possible. Drugs which specifically targeted to infected cells with ACE2 such as chloroquine are preferred in COVID-19 therapy.","type":"Research","database":"MedRxiv","created":"2020-03-29"},{"id":55,"name":"Medical treatment of 55 patients with COVID-19 from seven cities in northeast China who fully recovered: a single-center, retrospective, observational study","author":"Lichao Fan, Chang Liu, Na Li, Huan Liu, Ye Gu, Yongyu Liu, Yu Chen","doi":"10.1101\/2020.03.28.20045955","abstract":"Background: COVID-19 is an emerging disease caused by the SARS-CoV-2 virus; no specific medication has been identified to date. We aimed to investigate the administered medications and intervention times for patients who completely recovered from COVID-19. Methods: This single-center, retrospective, and observational study included 55 patients with COVID-19 who were transferred to Shenyang Sixth People's Hospital between January 20 and March 15, 2020. Demographic information, symptoms, laboratory indicators, treatment processes, and clinical outcomes were collected. Administered drugs and intervention times were compared in 47 and eight patients with mild and severe symptoms, respectively. Findings: All 55 patients recovered. Fifty-three patients (96.36%) received antiviral therapy, including 45 in the mild group (median treatment: 14 days; 17 received umifenovir) and all eight severe-group patients (median treatment: 17.5 days; four received lopinavir\/ritonavir). Twenty-nine patients (52.72%) were administered antibiotics, including 21 in the mild group (median treatment: 13.5 days; 15 received moxifloxacin) and all eight in the severe group (median treatment: 9 days; two received linezolid). Moreover, seven patients (12.72%) were treated with glucocorticoids and nine (16.36%) with immunomodulators. Interpretation: Given the 100% recovery rate, early administration of antiviral drugs can be considered. Umifenovir may benefit patients with mild symptoms, while lopinavir\/ritonavir may benefit those with severe symptoms. Prophylactic administration of common antibiotics may reduce the risk of co-infection. The use of glucocorticoids is usually not necessary.","type":"Research","database":"MedRxiv","created":"2020-03-29"},{"id":53,"name":"Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial","author":"Zhaowei Chen, Jijia Hu, Zongwei Zhang, Shan Jiang, Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu, Zhan Zhang","doi":"10.1101\/2020.03.22.20040758","abstract":"Aims: Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19. Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg\/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. Key findings: For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 32) compared with the control group (54.8%, 17 of 32). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.","type":"Research","database":"MedRxiv","created":"2020-03-29"},{"id":52,"name":"Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19 Infection- A Systematic Literature Review","author":"Krishan Mohan Kapoor, Aanandita Kapoor","doi":"10.1101\/2020.03.24.20042366","abstract":"Background: Coronavirus pandemic is currently a global public health emergency. At present, no pharmacological treatment is known to treat this condition, and there is a need to review the available treatments. Objective: While there have been studies to describe the role of chloroquine and hydroxychloroquine in various viral conditions, there is limited information about the use of them in COVID-19. This systematic review aims to summarize the available evidence regarding the role of chloroquine in treating coronavirus infection. Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used for this review. A literature search was performed using PUBMED & Google Scholar to find articles about the role of CQ in COVID-19 patients. Results: We included 19 publications (Five published articles, three letters\/correspondence, one commentary, five pre-proofs of accepted articles, one abstract of yet to be published article, and four were pre-prints (not yet peer-reviewed) articles) in this systematic review. All the articles mentioned about the role of chloroquine and \/or hydroxychloroquine in limiting the infection with SARS-CoV-2 (the virus causing COVID-19). Conclusions: There is theoretical, experimental, preclinical and clinical evidence of the effectiveness of chloroquine in patients affected with COVID-19. There is adequate evidence of drug safety from the long-time clinical use of chloroquine and hydroxychloroquine in other indications. More data from ongoing and future trials will add more insight into the role of chloroquine and hydroxychloroquine in COVID-19 infection.","type":"Review","database":"MedRxiv","created":"2020-03-29"},{"id":49,"name":"Are certain drugs associated with enhanced mortality in COVID-19?","author":"Goldstein MR, Poland GA, Graeber CW","doi":"10.1093\/qjmed\/hcaa103","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-26"},{"id":48,"name":"Recommendation for the diagnosis and treatment of novel coronavirus infection in children in Hubei (Trial version 1).","author":"Pediatric Branch of Hubei Medical Association; Pediatric Branch of Wuhan Medical Association; Pediatric Medical Quality Control Center of Hubei","doi":"10.1177\/0022034520914246","abstract":"Since December 2019, a cluster of patients have been diagnosed to be infected with 2019 novel coronavirus (2019-nCoV) in Wuhan, China. The epidemic has been spreading to other areas of the country and abroad. A few cases have progressed rapidly to acute respiratory distress syndrome and\/or multiple organ function failure. The epidemiological survey has indicated that the general population is susceptible to 2019-nCoV. A total of 14 children (6 months to 14 years of age, including 5 cases in Wuhan) have been confirmed to be infected with 2019-nCoV in China so far. In order to further standardize and enhance the clinical management of 2019-nCoV infection in children, reduce the incidence, and decrease the number of severe cases, we have formulated this diagnosis and treatment recommendation according to the recent information at home and abroad.","type":"Other","database":"PubMed","created":null},{"id":46,"name":"The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China.","author":"Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, Wang J, Qin Y, Zhang X, Yan X, Zeng X, Zhang S","doi":"10.1016\/j.clim.2020.108393","abstract":"The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine\/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.","type":"Comment","database":"PubMed","created":"2020-03-24"},{"id":45,"name":"Potential covalent drugs targeting the main protease of the SARS-CoV-2 coronavirus.","author":"Liu S, Zheng Q, Wang Z","doi":"10.1093\/bioinformatics\/btaa224","abstract":"Since December 2019, the newly identified coronavirus SARS-CoV-2 has caused a massive health crisis worldwide and resulted in over 70,000 COVID-19 infections so far. Clinical drugs targeting SARS-CoV-2 are urgently needed to decrease the high fatality rate of confirmed COVID-19 patients. Traditional de novo drug discovery needs more than 10 years, so drug repurposing seems the best option currently to find potential drugs for treating COVID-19.","type":"Research","database":"PubMed","created":"2020-03-31"},{"id":44,"name":"Coronavirus disease 2019 (COVID-19) and anti-rheumatic drugs.","author":"Georgiev T","doi":"10.1007\/s00296-020-04570-z","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-29"},{"id":43,"name":"COVID-19, rheumatic diseases and immunosuppressive drugs: an appeal for medication adherence.","author":"Venerito V, Lopalco G, Iannone F","doi":"10.1007\/s00296-020-04566-9","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-29"},{"id":41,"name":"COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?","author":"Sargiacomo C, Sotgia F, Lisanti MP","doi":"10.18632\/aging.103001","abstract":"COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.","type":"Review","database":"PubMed","created":"2020-03-29"},{"id":40,"name":"A randomized trial of instructor-led training versus video lesson in training health care providers in proper donning and doffing of personal protective equipment","author":"Christensen L, Rasmussen CS, Benfield T, Franc JM","doi":"10.1017\/dmp.2020.56","abstract":"This study compared live instructor-led training in Personal Protective Equipment (PPE) donning and doffing with video-based instruction. It assessed the difference in performance between (i) attending one instructor-led training session in donning and doffing PPE one month prior to assessment, and (ii) watching training videos over the month.","type":"Research","database":"PubMed","created":"2020-03-29"},{"id":39,"name":"High-flow nasal-oxygenation-assisted fibreoptic tracheal intubation in critically ill patients with COVID-19 pneumonia: a prospective randomised controlled trial.","author":"Wu CN, Xia LZ, Li KH, Ma WH, Yu DN, Qu B, Li BX, Cao Y","doi":"10.1016\/j.bja.2020.02.020","abstract":"No abstract available","type":"Research","database":"PubMed","created":"2020-03-18"},{"id":38,"name":"COVID-19 treatment by repurposing drugs until the vaccine is in sight.","author":"Phadke M, Saunik S","doi":"10.1002\/ddr.21666","abstract":"Corona virus disease (COVID-19) has created pandemic in the world as declared by WHO on March 12, 2020. It is a viral disease caused by SARS-CoV 2 virus and has affected large populations in over 120 countries. There is no specific treatment available and management is empirical. Until such time that an effective vaccine is available for COVID-19 viral infection, one can repurpose known therapeutic drug molecules such as angiotensin receptor 2 blocker, a commonly used antihypertensive drug, to control COVID-19 virus from gaining entry into the host cell by blocking the angiotensin receptor. Clinical trials should also be undertaken to use statins, which are lipid-lowering drugs but have anti-inflammatory and immunomodulatory properties to prevent acute lung injury in COVID-19 infection.","type":"Comment","database":"PubMed","created":"2020-03-28"},{"id":36,"name":"Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics.","author":"Kalil AC","doi":"10.1001\/jama.2020.4742","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-23"},{"id":35,"name":"Cluster investigation Technical Guidelines for the 2019 Novel Coronavirus Pneumonia (COVID-19), China (1st Trial Version).","author":"Epidemiology Working Group, Strategy and Policy Working Group for NCIP Epidemic Response","doi":"10.3760\/cma.j.issn.0254-6450.2020.0006","abstract":"No abstract available","type":"Other","database":"PubMed","created":"2020-02-18"},{"id":34,"name":"Clinical trials for the treatment of Coronavirus disease 2019 (COVID-19): A rapid response to urgent need.","author":"Zhang T, He Y, Xu W, Ma A, Yang Y, Xu KF","doi":"10.1007\/s11427-020-1660-2","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-02-28"},{"id":33,"name":"Drug interaction monitoring of lopinavir \/ ritonavir in COVID-19 patients with cancer.","author":"Zheng XW, Tao G, Zhang YW, Yang GN, Huang P","doi":"10.3760\/cma.j.cn112138-20200219-00097","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-02-29"},{"id":32,"name":"Covid-19: cases grow in US as Trump pushes promise of a malaria drug.","author":"Tanne JH","doi":"10.1136\/bmj.m1155","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-19"},{"id":31,"name":"Misguided drug advice for COVID-19.","author":"FitzGerald GA","doi":"10.1126\/science.abb8034","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-19"},{"id":30,"name":"Covid-19: trials of four potential treatments to generate \"robust data\" of what works.","author":"Sayburn A","doi":"10.1136\/bmj.m1206","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-23"},{"id":28,"name":"Interpretation of pathological changes for \"Guidelines for the Diagnosis and Treatment of COVID-19 by the National Health Commission (Trial Version 7)","author":"Ding YQ, Bian XW","doi":"10.3760\/cma.j.cn112151-20200318-00221","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-25"},{"id":26,"name":"Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?","author":"Esler M, Esler D","doi":"10.1097\/HJH.0000000000002450","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-10"},{"id":25,"name":"Use of antiviral drugs to reduce COVID-19 transmission.","author":"Mitj\u00e0 O, Clotet B","doi":"10.1016\/S2214-109X(20)30114-5","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-18"},{"id":22,"name":"Non-steroidal anti-inflammatory drugs and covid-19.","author":"Little P","doi":"10.1136\/bmj.m1185","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-26"},{"id":21,"name":"Antihypertensive drugs and risk of COVID-19?","author":"Tignanelli CJ, Ingraham NE, Sparks MA, Reilkoff R, Bezdicek T, Benson B, Schacker T, Chipman JG, Puskarich MA","doi":"10.1016\/S2213-2600(20)30158-2","abstract":"No abstract available","type":"Comment","database":"PubMed","created":"2020-03-25"},{"id":20,"name":"Clinical trial analysis of 2019-nCoV therapy registered in China.","author":"Zhang Q, Wang Y, Qi C, Shen L, Li J","doi":"10.1002\/jmv.25733","abstract":"So far, there is a lack of effective drugs for the new coronavirus pneumonia. With more and more patients diagnosed, China has carried out more than 100 clinical studies of new coronavirus infection, including antiviral drugs, antimalarial drugs, glucocorticoids, plasma therapy, virus vaccine, and other Western drugs, while Chinese medicine research accounted for half of the studies. Most of the trials were initiated by investigators and the study period would last for 1 to 11 months. The primary endpoints included symptom improvement and virus nucleic acid turning negative, but the optimal endpoint has not been determined. Although the final results of studies will take a long time to complete, the interim research data may provide some help for the current urgent demand for drug treatment. Compared with that of during SARS period in 2003, China has the stronger capability to carry out clinical trials of new drugs in emergency period.","type":"Review","database":"PubMed","created":"2020-02-27"},{"id":19,"name":"Interpretation of \"Guidelines for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Infection by the National Health Commission (Trial Version)","author":"Lin L, Li TS","doi":"10.3760\/cma.j.issn.0376-2491.2020.0001","abstract":"the National Health Commission of the People's Republic of China publish the guidelines for the diagnosis and treatment of novel coronavirus (2019-nCoV) infection (trial version 5) .With the awareness and understanding of the disease, the guidelines have been revised for recognize, treat, and prevent diseases. Then, what are the contents of the fifth edition of the guide issued updated compared to the fourth edition, now, learn together.","type":"Comment","database":"PubMed","created":"2020-02-06"},{"id":18,"name":"Expert recommendations on the management of patients with advanced non-small cell lung cancer during epidemic of COVID-19 (Trial version).","author":"Lung Cancer Study Group, Chinese Thoracic Society, Chinese Medical Association; Chinese Respiratory Oncology Collaboration","doi":"10.3760\/cma.j.cn112147-20200221-00138","abstract":"The outbreak of coronavirus disease 2019 (COVID-19) has become a public health emergency of major international concern. Given the systemic immunosuppressive state caused by malignancy and anticancer treatments, patients with advanced lung cancer may be at a higher risk of COVID-19 infection. During epidemic of COVID-19, a guideline for the optimal management of patients with advanced lung cancer urgently needs to be proposed to distinguish the symptoms of COVID-19 and the side effects of antitumor drugs. This network questionnaire survey was conducted on the lung cancer group of the Chinese Thoracic Society, Chinese Medical Association; the lung cancer group of the Chinese Society of Clinical Oncology Youth Committee; and the Chinese Respiratory Oncology Collaboration. 321 valid questionnaires were received. Based on the guidelines on lung cancer and the results of the questionnaires, a consensus was reached. During the epidemic of COVID-19, We recommended that patients with advanced NSCLC should be treated as outpatients as possible at the nearest medical center; Patients who need to be hospitalized for antitumor treatment should be excluded from COVID-19 infection; More intensive attention should be paid to identification of COVID-19-related symptoms and adverse reactions caused by the malignancy or antitumor treatments. Stronger personal protection should be made for advanced NSCLC patients; An intentional postponing of antitumor treatment should be considered according to patient performance status. Treatment strategies should be made according to different types of advanced NSCLC patients and efficacy and toxicity of drugs.","type":"Comment","database":"PubMed","created":"2020-03-02"},{"id":17,"name":"Drug targets for corona virus: A systematic review.","author":"Manisha Prajapat, Phulen Sarma, Nishant Shekhar, Pramod Avti, Shweta Sinha, Hardeep Kaur, Subodh Kumar, Anusuya Bhattacharyya, Harish Kumar, Seema Bansal, and Bikash Medhi","doi":"10.4103\/ijp.IJP_115_20","abstract":"The 2019-novel coronavirus (nCoV) is a major source of disaster in the 21<sup>th<\/sup> century. However, the lack of specific drugs to prevent\/treat an attack is a major need at this current point of time. In this regard, we conducted a systematic review to identify major druggable targets in coronavirus (CoV). We searched PubMed and RCSB database with keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The search identified seven major targets (spike protein, envelop protein, membrane protein, protease, nucleocapsid protein, hemagglutinin esterase, and helicase) for which drug design can be considered. There are other 16 nonstructural proteins (NSPs), which can also be considered from the drug design perspective. The major structural proteins and NSPs may serve an important role from drug design perspectives. However, the occurrence of frequent recombination events is a major deterrent factor toward the development of CoV-specific vaccines\/drugs.","type":"Review","database":"PubMed","created":"2020-03-10"},{"id":14,"name":"Guide to the Forensic Pathology Practice on Death Cases Related to Corona Virus Disease 2019 COVID-19).","author":"Mao Dan-mi, Zhou Nan, Zheng Da, Yu Jia-cheng, Zhao Qian-hao, Luo Bin, Guan Da-wei, Zhou Yi-wu, Hh Bing-jie, Cheng Jian-ding","doi":"10.12116\/j.issn.1004-5619.2020.01.003","abstract":"Autopsy is of great significance to the elucidation of the pathological changes, pathogenesis and cause of death of corona virus disease 2019 \uff08COVID-19\uff09 and can provide theoretical basis for more scientific and accurate prevention and control of the outbreak. Based on related laws and regulations, such as Law of the People's Republic of China on Prevention and Control of Infectious Diseases, the clinical manifestations and epidemiological characteristics of COVID-19, and the related guidelines on the prevention and control of the outbreak, combined with the practical work of forensic pathology examination, the Guide to the Forensic Pathology Practice on Death Cases Related to Corona Virus Disease 2019 \uff08COVID-19\uff09 \uff08Trial Draft\uff09 has been developed. This guide includes information on the background investigation of the cases, autopsy room requirements, personal prevention and protections, external examinations, autopsy, auxiliary examinations, and so on. This guide can be used as a reference by forensic and pathological examination institutions, as well as examination staff.","type":"Other","database":"PubMed","created":"2020-02-24"},{"id":12,"name":"Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial.","author":"Zhou YH, Qin YY, Lu YQ, Sun F, Yang S, Harypursat V, Tang SQ, Huang YQ, He XQ, Zeng YM, Li Y, Xu XL, Zhao T, Chen YK","doi":"10.1097\/CM9.0000000000000791","abstract":"BACKGROUND: At the end of 2019, a novel coronavirus outbreak emerged in Wuhan, China, and its causative organism has been subsequently designated the 2019 novel coronavirus (2019-nCoV). The virus has since rapidly spread to all provinces and autonomous regions of China, and to countries outside of China. Patients who become infected with 2019-nCoV may initially develop mild upper respiratory tract symptoms. However, a significant fraction of these patients goes on to subsequently develop serious lower respiratory disease. The effectiveness of adjunctive glucocorticoid therapy uses in the management of 2019-nCoV infected patients with severe lower respiratory tract infections is not clear, and warrants further investigation.\r\n\r\nMETHODS: The present study will be conducted as an open-labelled, randomised controlled trial. We will enrol 48 subjects from Chongqing Public Health Medical Center. Each eligible subject will be assigned to an intervention group (methylprednisolone via intravenous injection at a dose of 1-2mg\/kg\/day for 3 days) or a control group (no glucocorticoid use) randomly, at a 1:1 ratio. Subjects in both groups will be invited for 28 days of follow-up which will be scheduled at 4 consecutive visit points. We will use the clinical improvement rate as our primary endpoint. Secondary endpoints include the timing of clinical improvement after intervention, duration of mechanical ventilation, duration of hospitalization, overall incidence of adverse events, as well as rate of adverse events at each visit, and mortality at 2 and 4 weeks.\r\n\r\nDISCUSSION: The present coronavirus outbreak is the third serious global coronavirus outbreak in the past two decades. Oral and parenteral glucocorticoids have been used in the management of severe respiratory symptoms in coronavirus-infected patients in the past. However, there remains no definitive evidence in the literature for or against the utilization of systemic glucocorticoids in seriously ill patients with coronavirus-related severe respiratory disease, or indeed in other types of severe respiratory disease. In this study, we hope to discover evidence either supporting or opposing the systemic therapeutic administration of glucocorticoids in severe coronavirus disease 2019 (COVID-19) patients.\r\n\r\nTRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR2000029386, http:\/\/www.chictr.org.cn\/showproj.aspx?proj=48777.","type":"Other","database":"PubMed","created":"2020-03-04"},{"id":11,"name":"Drug treatment options for the 2019-new coronavirus (2019-nCoV).","author":"Lu H","doi":"10.5582\/bst.2020.01020","abstract":"As of January 22, 2020, a total of 571 cases of the 2019-new coronavirus (2019-nCoV) have been reported in 25 provinces (districts and cities) in China. At present, there is no vaccine or antiviral treatment for human and animal coronavirus, so that identifying the drug treatment options as soon as possible is critical for the response to the 2019-nCoV outbreak. Three general methods, which include existing broad-spectrum antiviral drugs using standard assays, screening of a chemical library containing many existing compounds or databases, and the redevelopment of new specific drugs based on the genome and biophysical understanding of individual coronaviruses, are used to discover the potential antiviral treatment of human pathogen coronavirus. Lopinavir \/Ritonavir, Nucleoside analogues, Neuraminidase inhibitors, Remdesivir, peptide (EK1), abidol, RNA synthesis inhibitors (such as TDF, 3TC), anti-inflammatory drugs (such as hormones and other molecules), Chinese traditional medicine, such ShuFengJieDu Capsules and Lianhuaqingwen Capsule, could be the drug treatment options for 2019-nCoV. However, the efficacy and safety of these drugs for 2019- nCoV still need to be further confirmed by clinical experiments.","type":"Review","database":"PubMed","created":"2020-01-27"},{"id":10,"name":"Facts and reflections on COVID-19 and anti-hypertensives drugs.","author":"Marin GH","doi":"10.5582\/ddt.2020.01017","abstract":"Based on some publications that associate SARS-CoV-2 infection with the use of anti-hypertensive drug groups such as angiotensin-converting-enzyme inhibitors (e.g. enalapril) or angiotensin II receptor blockers (e.g. losartan), many patients from South America, Central America or Spain, have stopped or intend to interrupt their treatments with these drugs. Hence, it may exist ominous consequences due to this drop out. For this reason, it is necessary to quickly warn about this situation and the risks associated with it.","type":"Comment","database":"PubMed","created":"2020-03-25"},{"id":8,"name":"A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.","author":"Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Do","doi":"10.1056\/NEJMoa2001282","abstract":"No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.","type":"Research","database":"PubMed","created":"2020-03-17"},{"id":6,"name":"Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model.","author":"Fan HH, Wang LQ, Liu WL, An XP, Liu ZD, He XQ, Song LH, Tong YG","doi":"10.1097\/CM9.0000000000000797","abstract":"Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those without such facilities or 2019-novel coronavirus (2019-nCoV). This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV related coronavirus model.","type":"Research","database":"PubMed","created":"2020-03-05"},{"id":5,"name":"The Trial of Chloroquine in the Treatment of Corona Virus Disease 2019 \uff08COVID-19\uff09 and Its Research Progress in Forensic Toxicology.","author":"Duan YJ, Liu Q, Zhao SQ, Huang F, Ren L, Liu L1 Zhou YW","doi":"10.12116\/j.issn.1004-5619.2020.02.001","abstract":"Chloroquine is a long-established prescription drug that is often used clinically to treat malaria and connective tissue diseases. Since December 2019, COVID-19 \uff08corona virus disease 2019\uff09 outbreaks caused by SARS-CoV-2 \uff08severe acute respiratory syndrome coronavirus 2\uff09 has occurred in China and many countries around the world. Due to the lack of drugs against COVID-19, the disease spreads rapidly and the mortality rate is relatively high. Therefore, specific drugs against SARS-CoV-2 need to be quickly screened. The antimalarial drug Chloroquine phosphate which has already been approved is confirmed to have an anti-SARS-CoV-2 effect and has been included in diagnostic and therapeutic guidelines. However, awareness of the risk of chloroquine phosphate causing acute poisoning or even death should be strengthened. The dosage used according to current clinical recommended dosage and course of treatment are larger than that of previous treatment of malaria. Many provinces have required close clinical monitoring of adverse reactions. This paper reviews the pharmacological effects, poisoning and toxicological mechanisms, in vivo metabolism and distribution, and forensic issues of chloroquine drugs, in order to provide help to forensic practice and clinical work.","type":"Review","database":"PubMed","created":"2020-03-24"},{"id":4,"name":"Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19?","author":"Sophie Alexandra Baron, Christian Devaux, Philippe Colsona Didier, Raoulta, Jean-Marc Rolain","doi":"10.1016\/j.ijantimicag.2020.105944","abstract":"In December 2019, a new coronavirus, named SARS-CoV-2, has emerged from China causing pneumonia outbreaks first in the Wuhan region and have now spread worldwide because of its probable high transmission efficiency. Due to the lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the best\u00a0tool to find therapeutic solution. Chloroquine, remdesivir, lopinavir, ribavirin or ritonavir have shown efficacy to inhibit coronavirus in vitro. Teicoplanin, an antibiotic used to treat staphylococci infection, previously showed efficacy to inhibit the first stage\u00a0of MERS-coronarivus viral cycle\u00a0in human cells. This activity is conserved on the SARS-Cov-2,\u00a0thus placing teicoplanin as a potential treatment for patients with this virus.","type":"Research","database":"PubMed","created":"2020-03-12"},{"id":3,"name":"Discovering drugs to treat coronavirus disease 2019 (COVID-19).","author":"Liying Dong, Shasha Hu, Jianjun Gao","doi":"10.5582\/ddt.2020.01012","abstract":"The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.","type":"Research","database":"PubMed","created":null},{"id":2,"name":"Network-based drug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2.","author":"Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin, Feixiong Cheng","doi":"10.1038\/s41421-020-0153-3","abstract":"Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV\/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV\/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV\/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the \"<i>Complementary Exposure<\/i>\" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV\/SARS-CoV-2.","type":"Research","database":"PubMed","created":"2020-03-15"},{"id":1,"name":"Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates","author":"Yu Wai Chen, Chin-Pang Bennu Yiu, Kwok-Yin Wong","doi":"10.12688\/f1000research.22457.1","abstract":"We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL <sup>pro<\/sup>) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. \u00a0With the 3CL <sup>pro<\/sup> molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.\u00a0 The drugs Epclusa (velpatasvir\/sofosbuvir) and Harvoni (ledipasvir\/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.","type":"Research","database":"PubMed","created":"2020-02-20"}]}