Remdesivir is a Delayed Translocation Inhibitor of SARS CoV-2 Replication

Abstract

Remdesivir is a nucleoside analog approved by the FDA for treatment of COVID-19. Here, we present a 3.9-Å-resolution cryoEM reconstruction of a remdesivir-stalled RNA-dependent RNA polymerase complex, revealing full incorporation of three copies of remdesivir monophosphate (RMP) and a partially incorporated fourth RMP in the active site. The structure reveals that RMP blocks RNA translocation after incorporation of three bases following RMP, resulting in delayed chain termination, which can guide the rational design of improved antiviral drugsFunding: This work was supported in part by Welch Foundation grantsF-1604 (to K.A.J.) and F-1938 (to D.W.T.), National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) R01AI110577 (to K.A.J) and National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) R01114223 (to K.A.J.) and R35GM138348 (to D.W.T.), Army Research Office Grant W911NF-15-1-0120(to D.W.T.), and a Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation Medical Research Award (to D.W.T.). D.W.T is a CPRIT Scholar supported by the Cancer Prevention andResearch Institute of Texas (RR160088) and an Army Young Investigator supported by the Army Research Office (W911NF-19-1-0021).Conflict of Interest: All authors declare no competing interests.