Peptide boronic acids, substrate analogs, inhibit chymase, and histamine release from rat mast cells.
Peptide boronic acids, such as methoxysuccinyl-Ala-Ala-Pro-(L)boro-Phe-OH, its pinacol ester, and t-butyloxycarbonyl-Phe-Pro-(L)boro-Phe-pinacol, inhibited the activity of chymase from connective tissue mast cells approximately 40- to 80-fold more than atypical chymase from mucosal mast cells, and did not inhibit trypsin. Only peptide boronic acids containing "L" forms of boronic acids were inhibitory. The Ki values of these peptide boronic acids for chymase were in the 60-170 nM concentration range, like those of the natural inhibitors tested, but all the natural inhibitors tested except Eglin C and chymostatin inhibited both chymase and trypsin. Thus these peptide boronic acids should be useful for selective inhibition of chymase with less inhibitory activity for atypical chymase and without inhibition of trypsin. These peptide boronic acids markedly inhibited histamine release induced by anti-rat immunoglobulin E, suggesting that chymase in connective tissue mast cells plays some role in the process of histamine release. These peptides are assumed to be therapeutically useful for treatment of allergic inflammations catalyzed by chymase.
Kato
Y
Y
Division of Enzyme Chemistry, University of Tokushima.
Kido
H
H
Fukusen
N
N
Katunuma
N
N
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D053818:Chymases; D006636:Histamine Release / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008407:Mast Cells / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors
D001897:Boronic Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases