D. Bromme et al., POTENT INACTIVATION OF CATHEPSIN-S AND CATHEPSIN-L BY PEPTIDYL (ACYLOXY)METHYL KETONES, Biological chemistry Hoppe-Seyler, 375(5), 1994, pp. 343-347
Peptidyl (acyloxy)methyl ketones (Z-Aa-Aa-CH2-OCO-R), a new class of i
rreversible inhibitors whose chemical reactivity can be modulated by v
arying the substitution pattern of the carboxylate leaving group, are
shown to be extremely potent inactivators of the lysosomal cysteine pr
oteinases cathepsin L and cathepsin S. The highest k(2)/K-i values mea
sured were found to exceed 10(6) M-ls-l for both cathepsin i, and cath
epsin S. The rate of inactivation can be controlled by varying the dip
eptidyl moiety or the carboxylate leaving group, with the second-order
rate constants for both enzymes found to be strongly dependent on the
p K,values of the leaving group. The specificities of the cathepsins
S and L reveal a different selectivity towards the nature of substitut
ion of the aryl P' leaving group of the inhibitor. This new inhibitor
class opens the possibility of the design of selective and specific in
hibitors for lysosomal cysteine proteinases.