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J Proteome Res
. 2020 Jul 21.
doi: 10.1021/acs.jproteome.0c00392. Online ahead of print.
Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19
Minchen Chien, Thomas K Anderson, Steffen Jockusch, Chuanjuan Tao, Xiaoxu Li, Shiv Kumar, James J Russo, Robert N Kirchdoerfer, Jingyue Ju
- PMID: 32692185
- DOI: 10.1021/acs.jproteome.0c00392
Abstract
SARS-CoV-2 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 (the triphosphates of Sofosbuvir, Alovudine and AZT) inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). We also demonstrated that a library of additional nucleotide analogues terminate RNA synthesis catalyzed by the SARS-CoV-2 RdRp, a well-established drug target for COVID-19. Here, we used polymerase extension experiments to demonstrate that the active triphosphate form of Sofosbuvir (an FDA-approved hepatitis C drug), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the molecular insight gained from the previous studies, we selected the active triphosphate forms of six other anti-viral agents, Alovudine, Tenofovir alafenamide, AZT, Abacavir, Lamivudine and Emtricitabine, for evaluation as inhibitors of the SARS-CoV-2 RdRp, and demonstrated the ability of these viral polymerase inhibitors to be incorporated by SARS-CoV-2 RdRp, where they terminate further polymerase extension with varying efficiency. These results provide a molecular basis for inhibition of the SARS-CoV-2 RdRp by these nucleotide analogues. If sufficient efficacy of some of these FDA-approved drugs in inhibiting viral replication in cell culture is established, they may be explored as potential COVID-19 therapeutics.