Portal de Periódicos da CAPES

Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors

2021; American Chemical Society; Volume: 65; Issue: 4 Linguagem: Inglês

10.1021/acs.jmedchem.1c00509

1520-4804

Naoya Kitamura, M. Sacco, Chunlong Ma, Yanmei Hu, Julia A. Townsend, Xiangzhi Meng, Fushun Zhang, Xiujun Zhang, Mandy Ba, Tommy Szeto, Adis Kukuljac, Michael T. Marty, D. Schultz, Sara Cherry, Yan Xiang, Yu Chen, Jun Wang,

Protein Structure and Dynamics

The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II, and XII, with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, 23R (Jun8-76-3A) that is structurally distinct from the canonical Mpro inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 Mpro with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.