Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir.

ABSTRACT: The SARS-CoV-2 main protease (M ^pro ) is the drug target of Pfizer’s oral drug Paxlovid. The emergence of SARS-CoV-2 variants with mutations in M ^pro raised the alarm of potential drug resistance. In this study, we identified 100 naturally occurring M ^pro mutations located at the nirmatrelvir binding site, among which 20 mutants, including S144M/F/A/G/Y, M165T, E166G, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to the wild-type (k _cat /K _m <10-fold change) and resistance to nirmatrelvir (K _i >10-fold increase). X-ray crystal structures were determined for seven representative mutants with and/or without GC-376/nirmatrelvir. Viral growth assay showed that M ^pro mutants with reduce

SUBMITTER: Hu Y 

PROVIDER: S-EPMC9479041 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature