The P132H mutation in the main protease of Omicron SARSCoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition  

作　　者：Michael Dominic Sacco Yanmei Hu Maura Verenice Gongora Flora Meilleur Michael Trent Kemp Xiujun Zhang Jun Wang Yu Chen 

机构地区：[1]Department of Molecular Medicine,Morsani College of Medicine,University of South Florida,Tampa,FL,USA. [2]Department of Medicinal Chemistry,Ernest Mario School of Pharmacy,Rutgers,the State University of New Jersey,Piscataway,NJ,USA. [3]Department of Molecular and Structural Biochemistry,North Carolina State University,Raleigh,NC,USA. [4]Neutron Scattering Division,Oak Ridge National Laboratory,Oak Ridge,TN,USA.

出　　处：《Cell Research》2022年第5期498-500,共3页细胞研究（英文版）

基　　金：the Spallation Neutron Source(Oak Ridge National Laboratory),a DOE Office of Science User Facility.This research was supported by the National Institutes of Health(NIH)(grants AI147325,AI157046,and AI158775)to J.W.We thank Eric M Lewandowski for reviewing this paper.

摘　　要：Dear Editor,The ongoing SARS-CoV-2 pandemic continues to be a significant threat to global health.First reported in November 2021,the Omicron variant(B.1.1.529)is more transmissible and can evade immunity better than previous SARS-CoV-2 variants,fueling an unprecedented surge in cases.To produce functional proteins from its polyprotein,SARS-CoV-2 relies on the cysteine proteases Nsp3/papain-like protease(PLpro)and Nsp5/main protease(Mpro)/3C-like protease to cleave at three and more than 11 sites,respectively.1 Therefore,Mpro and PLpro inhibitors are considered to be one of the most promising SARS-CoV-2 antivirals.On December 22,2021,the Food and Drug Administration(FDA)issued an Emergency Use Authorization(EUA)for PAXLOVID,a ritonavir-boosted formulation of nirmatrelvir.Nirmatrelvir is a first-in-class orally bioavailable SARSCoV-2 Mpro inhibitor.2 Thus,the scientific community must vigilantly monitor potential mechanisms of drug resistance,especially because SARS-CoV-2 is naïve to Mpro inhibitors.Mutations have been well identified in variants to this point.3 Notably,Omicron Mpro(OMpro)harbors a single mutation—P132H.In this study,we characterized the enzymatic activity,drug inhibition,and structure of OMpro while evaluating the past and future implications of Mpro mutations.

关 键 词：immunity stability CATALYSIS 

分 类 号：R37[医药卫生—病原生物学] R563.1[医药卫生—基础医学]