Abstract
SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.
Highlights
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is a member of the Orthocoronavirinae subfamily[1]
We and others have demonstrated that Sofosbuvir triphosphate (SOF-TP) can terminate the reaction catalyzed by coronavirus RNA-dependent RNA polymerases (RdRps), it is not known whether Sofosbuvir terminated RNA will offer any resistance to the SARS-CoV-2 exonuclease-based proofreader
Considering the low toxicity of Sofosbuvir, its ability to be rapidly activated to the triphosphate form by cellular enzymes, and the high intracellular stability of Sofosbuvir triphosphate, Sayad et al initiated a COVID-19 treatment clinical trial with Sofosbuvir and Velpatasvir, which together form the combination hepatitis C virus (HCV) drug EPCLUSA20
Summary
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is a member of the Orthocoronavirinae subfamily[1]. In late January of 2020, before COVID-19 reached pandemic status, based on our analysis of the molecular structures and activities of hepatitis C viral inhibitors and a comparison of hepatitis C virus and coronavirus replication, we postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-210. Unlike many other RNA viruses, SARS-CoV and SARS-CoV-2 have very large genomes (~ 30 kb) that encode a 3′–5′ exonuclease (nsp14) that carries out p roofreading[23,24]; this activity is enhanced by the nsp[10] c ofactor[25] This exonuclease-based proofreader increases replication fidelity by removing mismatched nucleotides to maintain the viral genome integrity[26]. We and others have demonstrated that Sofosbuvir triphosphate (SOF-TP) can terminate the reaction catalyzed by coronavirus RdRps, it is not known whether Sofosbuvir terminated RNA will offer any resistance to the SARS-CoV-2 exonuclease-based proofreader. The current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials[20,21] is supported by these molecular level results
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