RT Journal Article
SR Electronic
T1 Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.18.997585
DO 10.1101/2020.03.18.997585
A1 Chien, Minchen
A1 Anderson, Thomas K.
A1 Jockusch, Steffen
A1 Tao, Chuanjuan
A1 Kumar, Shiv
A1 Li, Xiaoxu
A1 Russo, James J.
A1 Kirchdoerfer, Robert N.
A1 Ju, Jingyue
YR 2020
UL http://biorxiv.org/content/early/2020/03/20/2020.03.18.997585.abstract
AB 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.