The Remarkable Selectivity of Nirmatrelvir.

The SARS-CoV-2 main protease is among the most attractive targets for the development of therapeutic interventions for COVID-19. Successful candidate agents will not only possess potent on-target activity versus SARS-CoV-2 Mpro but also minimal polypharmacology versus human cysteine proteases. This Viewpoint explores the activity profile of the first approved SARS-CoV-2 Mpro inhibitor (Nirmatrelvir) versus a panel of cysteine proteases and considers the therapeutic implications of the data.