Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

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.

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

“…We recently demonstrated that Sofosbuvir terminated RNA is more resistant to the SARS‐CoV‐2 proofreading exonuclease than RNAs terminated by Remdesivir and natural nucleotides 64 . The higher resistance to exonuclease of Sofosbuvir‐RNA relative to the RNAs containing the natural nucleotide or Remdesivir can compensate for the apparently lower SARS‐CoV‐2 RdRp incorporation efficiency of Sofosbuvir triphosphate.…”

Considerations of the effects of commonly investigated drugs for COVID-19 in the cholesterol synthesis pathway

“…Deoxyribose-containing RdRp nucleotide analogs have been shown to be more resistant to the exonuclease proofreading complex than those containing ribose rings such as remdesivir. In this regard, sofosbuvir contains a deoxyribose that exhibits more resistance to this proofreading complex, providing more stability than remdesivir [38]. Trial results evaluating sofosbuvir efficacy against COVID-19 are encouraging.…”

Science’s Response to COVID-19

“…238 Inhibitors of other viral RdRps, e.g., sofosbuvir (another nucleoside-monophosphate prodrug), 239 approved for use against hepatitis-C virus, although only in conjunction with other drugs, have also entered trials. 240 Recent reports have indicated that sofosbuvir/daclatasvir may help reduce the number of patients with fatigue 1-month post CoVID-19 infection, although it did not significantly relieve virus-induced early symptoms. 241 (hydroxy)Chloroquine…”