Mutation Could Allow SARS-CoV-2 to Develop Resistance to Gilead’s Remdesivir, Suggests New Research

Researchers have identified how the Ebola virus and SARS-CoV-2 could mutate to develop resistance to treatment with Gilead Sciences’ (Foster City, CA, USA) investigational antiviral drug remdesivir.

Their study identified a single amino acid residue in the Ebola virus polymerase that conferred low-level resistance to remdesivir. More importantly, in addition to characterizing this particular mutation, the scientists related it to a resistance mutation observed in a similar structural motif of coronaviruses. Remdesivir is a nucleotide analog prodrug that has been clinically evaluated against both Ebola virus disease and COVID-19, and has recently received emergency use authorization (EUA) for the latter. Remdesivir was first characterized and evaluated as a potent inhibitor of the Ebola virus. The drug has also shown efficacy in mice and nonhuman primates against other highly pathogenic respiratory pathogens, including Nipah virus and both severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV). Furthermore, preliminary evidence from clinical evaluations indicate that remdesivir shortens the recovery time of hospitalized COVID-19 patients presumably by blocking RNA replication of SARS-CoV-2. Remdesivir has been biochemically shown to inhibit the activity of Ebola virus large (L) RNA-dependent RNA polymerase (RdRp) as a non-obligate delayed chain terminator.


In line with the FDA’s recommendation for researchers to identify and characterize how viruses become resistant to drugs in order to gain a better understanding of their mechanism of action, scientists at the US Centers for Disease Control and Prevention (CDC) attempted to further understand the mechanism of Ebola virus inhibition and to identify determinants of resistance that may arise upon treatment of patients with remdesivir. Importantly, such determinants may naturally be present in other filoviruses, either known or yet to cross over into the human population. They found that remdesivir’s mechanism of action is common to both the Ebola virus as well as SARS-CoV-2.

The team serially passaged recombinant Ebola viruses with subclinical concentrations of remdesivir and demonstrated the reduced susceptibility of these viruses to remdesivir after 35 passages. The scientists identified a single-nucleotide variant (SNV) that emerged across six independent remdesivir-selected Ebola virus lineages; this mutation resulted in a non-conservative amino acid substitution at residue 548 (F548S) in the fingers sub-domain of the Ebola virus L RdRp. The scientists also examined this mutation in several contexts: a cell-based minigenome, a cell-free biochemical polymerase assay, as well as in a full-length infectious recombinant Ebola virus. In the context of the infectious virus, the F548S substitution recapitulated the reduced susceptibility phenotype to remdesivir, and potentially showed a marginal decrease in viral fitness compared to wild type. Thus, the study importantly identified a molecular marker for reduced remdesivir susceptibility.

The findings have implications for the surveillance of filovirus sequences, for treatment of Ebola virus patients with remdesivir or other similarly acting inhibitors, and for the development of future anti- Ebola virus therapies. Furthermore, comparative structural modeling of the Ebola virus and SARS-CoV-2 RdRp domains indicate remdesivir targets the polymerases of Ebola viruses and coronaviruses similarly, such that the findings may have implications for remdesivir treatment of COVID-19 patients.

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