In Vitro Selection of Remdesivir-Resistant SARS-CoV-2 Demonstrates High Barrier to Resistance

In vitro selection of remdesivir-resistant SARS-CoV-2 revealed the emergence of a V166L substitution, located outside of the polymerase active site of the nsp12 protein, after 9 passages. V166L remained the only nsp12 substitution after 17 passages at a final concentration of 10 µM RDV, conferring a 2.3-fold increase in EC ₅₀ . When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC ₅₀ was observed, indicating a high in vitro barrier to RDV resistance.