A yeast-based system to study SARS-CoV-2 M ^pro structure and to identify nirmatrelvir resistant mutations.

ABSTRACT: The SARS-CoV-2 main protease (M ^pro ) is a major therapeutic target. The M ^pro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As M ^pro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as a proxy for M ^pro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays showed that an E166R substitution conferred strong nirmatrelvir resistance while an E166N mutation compromised activity. On the other hand, N142A and P132H mutations caused little to no change in dru

SUBMITTER: Ou J 

PROVIDER: S-EPMC9387140 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature