title: Comparative behaviour of calpain and cathepsin B toward peptidyl acyloxymethyl ketones, sulphonium methyl ketones and other potential inhibitors of cysteine proteinases.
abstract: Peptidyl acyloxymethyl ketones, previously established as potent inactivators of the lysosomal cysteine proteinase cathepsin B, were evaluated against smooth-muscle calpain, a member of the family of Ca(2+)-dependent cysteine proteinases. Only modest rates of time-dependent inhibition could be achieved, even with peptidyl affinity groups optimized for calpain and linked to a carboxylate leaving group of very low pKa [2,6-(CF3)2PhCOO-, pKa 0.58]. Selective inactivation of cathespin B versus calpain was consistently observed with this type of inhibitor. Examination of other potential inhibitors revealed a rank order of potency against calpain to be: peptidyl sulphonium methyl ketones > fluoromethyl ketones, diazomethyl ketones >> acyloxymethyl ketones, an order which differs sharply from that found for cathespin B.
authors: Syntex Research, Mississauga, Ontario, Canada.
authors: D H
authors: DH
authors: Pliura
authors: B J
authors: BJ
authors: Bonaventura
authors: R A
authors: RA
authors: Smith
authors: P J
authors: PJ
authors: Coles
authors: A
authors: A
authors: Krantz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002154:Calpain / Q000037:antagonists & inhibitors*; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D002645:Chickens; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D007659:Ketones / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013452:Sulfonium Compounds / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D010455:Peptides; D013452:Sulfonium Compounds; D002154:Calpain; D002401:Cathepsin B