Covalent inhibitors that use nitrile warheads are not uncommon. Of marketed drugs, the anti-COVID-19 agent nirmatrelvir (Supplementary table ) inhibits the SARS-CoV-2 main protease M pro by the reversible reaction of an active site cysteine residue with its nitrile moiety. Odanacatib (Supplementary Table ) was an anti-osteoporosis drug developed by Merck but terminated for increased risk of stroke ; it acts by reversible covalent binding to an active site cysteine residue of cathepsin K. Related analogs were prepared as inhibitors of the cysteine protease cruzain. A piperidinecarbonitrile PF-303 was prepared as a reversible covalent inhibitor of BTK (Supplementary Table ). While nitriles are in theory capable of reacting with nucleophilic residues (such as lysine, threonine, and serine residues), nitriles appear to be most reactive with cysteine residues.