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.

Duarte, Rodrigo R. R.Copertino, Dennis C.Iñiguez, Luis P.Marston, Jez L.Bram, YaronHan, YulingSchwartz, Robert E.Chen, ShuibingNixon, Douglas F.Powell, Timothy R.

10.1186/s10020-021-00356-6

Research curated

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 molecular docking analyses, with in 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’s 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 supports 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.

Source: PMC

Related molecules

Name	Synonyms	Genes
Flupentixol
Raloxifene
RNA dependent RNA polymerase	RDR, viral RNA polymerase, RdRp, nsp12	rep, ORF1a-1b, RdRp
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Atorvastatin	Lipitor, Sortis

Related interactions

Target	Drug	Type	Result
RNA dependent RNA polymerase	Atorvastatin	Computational	positive
RNA dependent RNA polymerase	Atorvastatin	In vitro	positive
RNA dependent RNA polymerase	Flupentixol	Computational	positive
3C-like protease	Flupentixol	Computational	positive
3C-like protease	Flupentixol	In vitro	negative
RNA dependent RNA polymerase	Flupentixol	In vitro	positive
RNA dependent RNA polymerase	Raloxifene	Computational	positive
3C-like protease	Raloxifene	Computational	positive
RNA dependent RNA polymerase	Raloxifene	In vitro	positive
3C-like protease	Atorvastatin	Computational	positive