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Volume 32, No 5, May 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 5, May 2022: 498-500

LETTERS TO THE EDITOR

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

Michael Dominic Sacco1 , Yanmei Hu2 , Maura Verenice Gongora1 , Flora Meilleur3,4 , Michael Trent Kemp1 , Xiujun Zhang1 , Jun Wang2,* , Yu Chen1,*

1Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
2Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
3Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA
4Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA
Correspondence: Jun Wang(junwang@pharmacy.rutgers.edu)Yu Chen(ychen1@usf.edu)

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 SARS-CoV-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.



https://doi.org/10.1038/s41422-022-00640-y

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