Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?

Cysteine proteases
are important targets for the discovery of novel
therapeutics for many human diseases. From parasitic diseases to cancer,
cysteine proteases follow a common mechanism, the formation of an
encounter complex with subsequent nucleophilic reactivity of the catalytic
cysteine thiol group toward the carbonyl carbon of a peptide bond
or an electrophilic group of an inhibitor. Modulation of target enzymes
occurs preferably by covalent modification, which imposes challenges
in balancing cross-reactivity and selectivity. Given the resurgence
of irreversible covalent inhibitors, can they impair off-target effects
or are reversible covalent inhibitors a better route to selectivity?
This Perspective addresses how small molecule inhibitors may achieve
selectivity for different cathepsins, cruzain, rhodesain, and falcipain-2.
We discuss target- and ligand-based designs emphasizing repurposing
inhibitors from one cysteine protease to others.