<i>In Vitro</i> Selection of Remdesivir-Resistant SARS-CoV-2 Demonstrates High Barrier to Resistance

Abstract

<i>In vitro</i> selection of remdesivir-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed the emergence of a V166L substitution, located outside of the polymerase active site of the Nsp12 protein, after 9 passages of a single lineage. V166L remained the only Nsp12 substitution after 17 passages (10 μM remdesivir), conferring a 2.3-fold increase in 50% effective concentration (EC₅₀). When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC₅₀ was observed, indicating a high <i>in vitro</i> barrier to remdesivir resistance.