Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase

Jingyue Ju, Xiaoxu Li, Shiv Kumar, Steffen Jockusch, Minchen Chien, Chuanjuan Tao, Irina Morozova, Sergey Kalachikov, Robert N. Kirchdoerfer, James J. Russo

10.1002/prp2.674

Research curated

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.

Source: BioRxiv

Related molecules

Name	Synonyms	Genes
Alovudine
Zidovudine	azidothymidine
RNA dependent RNA polymerase	RDR, viral RNA polymerase, RdRp, nsp12	rep, ORF1a-1b, RdRp
Tenofovir alafenamide
Sofosbuvir
Atazanavir

Related interactions

Target	Drug	Type	Result
RNA dependent RNA polymerase	Tenofovir alafenamide	In vitro	positive
RNA dependent RNA polymerase	Sofosbuvir	In vitro	positive
RNA dependent RNA polymerase	Alovudine	In vitro	positive
RNA dependent RNA polymerase	Atazanavir	Computational	positive
RNA dependent RNA polymerase	Zidovudine	In vitro	positive