The COVID pandemic has virtually affected everyone. With the majority of cases being mild, in some situations, the virus had caused serious lung damage. There is no treatment available for COVID, though a lot are under evaluation including antivirals. The Columbia Engineering researchers report that Sofosbuvir-terminated RNA is more resistant to the proofreader of SARS-CoV-2, the virus that causes COVID-19, than Remdesivir-terminated RNA. The results of the new study, published in the Nature Research journal Scientific Reports, support the use of the FDA-approved hepatitis C drug EPCLUSA--Sofosbuvir/Velpatasvir--in combination with other drugs in COVID-19 clinical trials.
The SARS-CoV-2 exonuclease-based proofreader maintains the accuracy of viral RNA genome replication to sustain virulence. Any effective antiviral targeting the SARS-CoV-2 polymerase must therefore display a certain level of resistance to this proofreading activity.
"We found that the RNA terminated by Sofosbuvir resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic," says the team's lead PI Jingyue Ju, Samuel Ruben-Peter G. Viele Professor of Engineering; Professor of Chemical Engineering and Pharmacology; Director, Center for Genome Technology & Biomolecular Engineering.
The new study builds upon earlier work the researchers have conducted. Last January, before COVID-19 reached a pandemic status, the team posited that EPCLUSA might inhibit SARS-CoV-2, the virus responsible for COVID-19. Their reasoning was based on the analysis of the molecular structures and activities of hepatitis C viral inhibitors and a comparison of the hepatitis C virus and coronavirus replication.
In a subsequent study, the researchers demonstrated that the active drug Sofosbuvir triphosphate is incorporated by SARS-CoV and SARS-CoV-2 polymerases, shutting down the polymerase reaction. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; currently, COVID-19 clinical trials with a number of hepatitis C drugs such as EPCLUSA and the combination of Sofosbuvir and Daclatasvir (which is similar to Velpatasvir) are ongoing in several countries.
Ju notes that a recent preprint from UC Berkeley indicates that a combination of Remdesivir and EPCLUSA increases Remdesivir's efficacy 25-fold in inhibiting SARS-CoV-2, the virus that causes COVID-19: "These results offer a molecular basis supporting the study of EPCLUSA in combination with Remdesivir for COVID-19 clinical trials."
