Potent and Selective Covalent Inhibition of the Papain-Like Protease from SARS-CoV-2

The most potent compound inhibited the papain-like protease with kinact/KI= 9,600 M−1 s−1, achieved sub-μM EC50 values against three SARS-CoV-2 variants in mammalian cell lines, and did not inhibit a panel of human deubiquitinases at >30 μM concentrations of inhibitor.