title: Inhibitory effect of di- and tripeptidyl aldehydes on calpains and cathepsins.
abstract: Eight different di- and tripeptidyl aldehyde derivatives, each having at its C-terminus an aldehyde analog of L-norleucine, L-methionine, or L-phenylalanine with a preceding L-leucine residue, were synthesized and tested for their inhibitory effects on several serine and cysteine endopeptidases. These compounds showed almost no inhibition of trypsin, and only weak inhibition of alpha-chymotrypsin and cathepsin H, while they exhibited marked inhibition of cathepsin B less than calpain II congruent to calpain I less than cathepsin L, being stronger in this order. The mode of inhibition of these cysteine proteinases was competitive for the peptide substrate used and inhibitor constants (Ki) were calculated from the Dixon plot. The best inhibitors found were: 4-phenyl-butyryl-Leu-Met-H for calpain I (Ki, 36 nM) and calpain II (Ki, 50 nM); acetyl-Leu-Leu-nLeu-H for cathepsin L (Ki, 0.5 nM); acetyl-Leu-Leu-Met-H for cathepsin B (Ki, 100 nM).
authors.affiliation: Department of Clinical Science and Laboratory Medicine, Kyoto University Faculty of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: M
authors.initials: M
authors.lastname: Kishi
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Higuchi
authors.forename: E
authors.initials: E
authors.lastname: Kominami
authors.forename: N
authors.initials: N
authors.lastname: Katunuma
authors.forename: T
authors.initials: T
authors.lastname: Murachi
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000447:Aldehydes; D004151:Dipeptides; D007202:Indicators and Reagents; D009842:Oligopeptides; D011480:Protease Inhibitors; D002403:Cathepsins; D002154:Calpain