PT  - JOURNAL ARTICLE
AU  - Michael D Sacco
AU  - Yanmei Hu
AU  - Maura V Gongora
AU  - Flora Meilleur
AU  - M Trent Kemp
AU  - Xiujun Zhang
AU  - Jun Wang
AU  - Yu Chen
TI  - The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition
AID  - 10.1101/2022.01.26.477774
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.26.477774
4099  - http://biorxiv.org/content/early/2022/01/27/2022.01.26.477774.short
4100  - http://biorxiv.org/content/early/2022/01/27/2022.01.26.477774.full
AB  - 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 this 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 some 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 characterize the enzymatic activity, drug inhibition, and structure of OMpro while evaluating the past and future implications of Mpro mutations.Competing Interest StatementThe authors have declared no competing interest.