Development of peptidyl α-keto-β-aldehydes as new inhibitors of cathepsin L — comparisons of potency and selectivity profiles with cathepsin B

We have utilized previously known substrate and inhibitor specificity profiles for the lysosomal cysteine protease, cathepsin L, to design a new series of putative inhibitors of this enzyme, based on di- and tri-peptidyl α-keto-β-aldehydes. Kinetic evaluation of these compounds revealed Z-Phe-Tyr(OBut)-COCHO, with a Ki=0.6 nM, to be the most potent, synthetic reversible inhibitor of cathepsin L reported to date.