Tweet
Pharmacol Res Perspect
. 2020 Dec;8(6):e00674.
doi: 10.1002/prp2.674.
Nucleotide analogues as inhibitors of SARS-CoV Polymerase
Jingyue Ju 1 2 3 , Xiaoxu Li 1 2 , Shiv Kumar 1 2 , Steffen Jockusch 1 4 , Minchen Chien 1 2 , Chuanjuan Tao 1 2 , Irina Morozova 1 2 , Sergey Kalachikov 1 2 , Robert N Kirchdoerfer 5 6 , James J Russo 1 2
Affiliations
- PMID: 33124786
- DOI: 10.1002/prp2.674
Abstract
SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected 3'-fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate, which are the active forms of two other anti-viral agents, Alovudine and AZT (an FDA-approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.
Keywords: COVID-19; RNA-dependent RNA polymerase; SARS-CoV; SARS-CoV-2; nucleotide analogue.