SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots.

ABSTRACT: SARS-CoV-2 main protease (Mpro) inhibitors are the first-line COVID-19 treatment. Nirmatrelvir is used worldwide, while ensitrelvir, licensed in Japan and Singapore, has received FDA fast-track designation. To facilitate population monitoring for viral resistance and guide next-generation inhibitor design, we investigated SARS-CoV-2 resistance and cross-resistance to ensitrelvir and nirmatrelvir. SARS-CoV-2 escape variants with high fitness and high ensitrelvir resistance were selected under clinically relevant concentrations in infectious cell culture assays. Using infectious cell culture, replicon, and Mpro assays, reverse genetics revealed synergistic combinations of resistance-associated substitutions (RAS), specifically M49L + S144A and M49L + S144A + T169I, that conferred high resist

SUBMITTER: Zhou Y 

PROVIDER: S-EPMC12529750 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature