Cysteine Protease Inhibitors
Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by a histidine residue. The next step is nucleophilic attack by the deprotonated cysteine's anionic sulfur on the peptide carbonyl carbon. In this step, a fragment of the substrate is released with an amine terminus, the histidine residue in the protease is restored to its deprotonated form, and a thioester intermediate linking the new carboxy-terminus of the substrate to the cysteine thiol is formed. The thioester bond is subsequently hydrolyzed to generate a carboxylic acid moiety on the remaining substrate fragment, while regenerating the free enzyme.
As might be expected an enzyme with a nucleophilic sulphur in the active site chloroketones have been shown to be potent inhibitors.
There are many other examples of covalent inhibitors described here
Updated 24 March 2020