This article is a Preprint
Preprints are preliminary research reports that have not been certified by peer review. They should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as established information.
Preprints posted online allow authors to receive rapid feedback and the entire scientific community can appraise the work for themselves and respond appropriately. Those comments are posted alongside the preprints for anyone to read them and serve as a post publication assessment.
Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir
Preprint
in En
| PREPRINT-BIORXIV
| ID: ppbiorxiv-497978
ABSTRACT
The SARS-CoV-2 main protease (Mpro) is the drug target of Pfizers oral drug Paxlovid. The emergence of SARS-CoV-2 variants with mutations in Mpro raised the alarm of potential drug resistance. In this study, we identified 100 naturally occurring Mpro 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 (kcat/Km <10-fold change) and resistance to nirmatrelvir (Ki >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 Mpro mutants with reduced enzymatic activity led to attenuated viral replication. Overall, our study identified several drug resistant hot spots that warrant close monitoring for possible clinical evidence of Paxlovid resistance. One Sentence SummaryPaxlovid resistant SARS-CoV-2 viruses with mutations in the main protease have been identified from clinical isolates.
cc_by_nc
Full text:
1
Collection:
09-preprints
Database:
PREPRINT-BIORXIV
Type of study:
Prognostic_studies
Language:
En
Year:
2022
Document type:
Preprint