Potent and selective inactivation of cysteine proteinases with N-peptidyl-O-acyl hydroxylamines.
A series of N-peptidyl-O-acyl hydroxylamines was synthesized and tested as inactivators of cysteine proteinases. Depending on the structure of the peptidyl residue of the inhibitors, rapid and complete irreversible inactivation of the lysosomal cathepsins, B, L and S, may be achieved. The most effective inhibitors display second-order rate constants of the inactivation in the range 10(5)-10(6) M-1.s-1. By contrast, the activity of the aminoendopeptidase cathepsin H is only negligibly affected by the N-terminal-protected peptidyl inhibitors.
Brömme
D
D
Institute of Biochemistry, Medical Faculty, Martin-Luther-University, Halle, German Democratic Republic.
Schierhorn
A
A
Kirschke
H
H
Wiederanders
B
B
Barth
A
A
Fittkau
S
S
Demuth
H U
HU
D000595:Amino Acid Sequence; D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors; D015853:Cysteine Proteinase Inhibitors; D018819:Dipeptidyl Peptidase 4; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006898:Hydroxylamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D015842:Serine Proteinase Inhibitors
D015853:Cysteine Proteinase Inhibitors; D006898:Hydroxylamines; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4