Inhibition of dynorphin converting enzymes from human spinal cord by N-peptidyl-O-acyl hydroxylamines.
Two cysteine proteinases, cleaving dynorphins A and B to enkephalins, were isolated from the human spinal cord. These enzymes were found to be competitively inhibited by a new class of synthetic inhibitors: N-peptidyl-O-acyl hydroxylamines. The most potent (Ki < 20 microM) were the N-terminally protected peptides Z-Phe-Phe-NHO-Ma and Boc-Phe-Gly-NHO-Bz, both containing hydrophobic amino acids at the P2 position. N-Peptidyl-O-acyl hydroxylamines were converted in water solution to the corresponding hydroxamic acids and no cleavage of the peptide bond within the inhibitor sequence was observed after prolonged incubation with the enzymes. It is anticipated that these synthetic compounds may serve as potential pharmacological tools for in vitro studies on dynorphin processing.
Silberring
J
J
Department of Drug Dependence Research, Karolinska Institute, Stockholm, Sweden.
Demuth
H U
HU
Brostedt
P
P
Nyberg
F
F
D000595:Amino Acid Sequence; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D011863:Radioimmunoassay; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*
D015853:Cysteine Proteinase Inhibitors; D006898:Hydroxylamines; D009842:Oligopeptides; D003546:Cysteine Endopeptidases; C063078:dynorphin converting enzyme