Inhibition of cathepsin B by peptidyl aldehydes and ketones: slow-binding behavior of a trifluoromethyl ketone.
Inhibition of the cysteine proteinase cathepsin B by a series of N-benzyloxycarbonyl-L-phenylalanyl-L-alanine ketones and the analogous aldehyde has been investigated. Surprisingly, whereas the aldehyde was found to be almost as potent a competitive reversible inhibitor as the natural peptidyl aldehyde, leupeptin, the corresponding trifluoromethyl ketone showed comparatively weak (and slow-binding) reversible inhibition. Evaluation of competitive hydration and hemithioketal formation in a model system led to a structure-activity correlation spanning several orders of magnitude in both cathepsin B inhibition constants (Ki) and model system equilibrium data (KRSH,apparent).
Smith
R A
RA
Syntex Research, Mississauga, Ontario, Canada.
Copp
L J
LJ
Donnelly
S L
SL
Spencer
R W
RW
Krantz
A
A
D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D002401:Cathepsin B / Q000032:analysis*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000447:Aldehydes; D001593:Benzyl Compounds; D004151:Dipeptides; D007202:Indicators and Reagents; D007659:Ketones; D002401:Cathepsin B