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

The main protease (M) of SARS-CoV-2 is a validated antiviral drug target. Several M inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including , , , and , 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, () that is structurally distinct from the canonical M inhibitor . Significantly, is highly selective compared with covalent inhibitors such as , especially toward host proteases. The cocrystal structure of SARS-CoV-2 M with revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered , one of the most potent and selective noncovalent SARS-CoV-2 M inhibitors reported to date, and a novel binding pocket in M that can be explored for inhibitor design.