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

• DOI: 10.1101/2022.06.28.497978
• Publication Date: 2022-06-29T06:40:10Z
• Authors: Yanmei Hu; Eric M. Lewandowski; Haozhou Tan; Xiaoming Zhang; Ryan T. Morgan; Xiujun Zhang; Lian M. C. Jacobs; Shane G. Butler; Maura V. Gongora; John Choy; Xufang Deng; Yu Chen; Jun Wang
• Keywords: 0301 basic medicine; Chemistry; 03 medical and health sciences; QD1-999; Article; 3. Good health

ABSTRACT The SARS-CoV-2 main protease (M pro ) is the drug target of Pfizer’s oral Paxlovid. emergence variants with mutations in M raised alarm potential resistance. In this study, we identified 100 naturally occurring located at 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 wild-type (k cat /K m <10-fold change) resistance (K i >10-fold increase). X-ray crystal structures were determined for seven representative mutants and/or without GC-376/nirmatrelvir. Viral growth assay that reduced led attenuated viral replication. Overall, our study several resistant hot spots warrant close monitoring possible clinical evidence Paxlovid One Sentence Summary viruses have been from isolates.