Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2

This preclinical study describes the design, synthesis, and evaluation of a series of covalent inhibitors targeting the SARS-CoV-2 papain-like protease (PLpro). The authors modified the noncovalent inhibitor GRL0617 by adding a peptidomimetic linker and various electrophilic warheads to target the catalytic cysteine (Cys111). An X-ray co-crystal structure confirmed the covalent binding mode. The findings highlight a promising chemical scaffold for further development of potential COVID-19 therapeutics.