Abstract
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention's Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.
Highlights
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19
We identified a single-nucleotide variant (SNV) that emerged across six independent remdesivir-selected Ebola virus (EBOV) lineages; this mutation resulted in a nonconservative amino acid substitution at residue 548 (F548S) in the fingers subdomain of the EBOV L RNA-dependent RNA polymerase (RdRp)
We showed that serial passaging of rEBOV/ZsG under subclinical remdesivir concentrations resulted in the emergence of a nonsynonymous substitution F548S near the base of conserved motif F, which forms a channel allowing for nucleotide triphosphate (NTP) entry [14]
Summary
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. Guidance from the Food and Drug Administration on antiviral product development recommends the characterization of in vitro-selected resistant viruses to define the mechanism of action and establish the specific antiviral activity. This is done routinely during the preclinical development of new antiviral therapies, to our knowledge, this has not been done for a Significance. Remdesivir is a nucleotide analog prodrug that has been evaluated in humans against acute Ebola virus disease; it recently received emergency use authorization for treating COVID-19. Our findings thereby indicate a consistent mechanism of action by remdesivir across genetically divergent RNA viruses causing diseases of high consequence in humans
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