Inhibition of matrix metalloproteinases by peptidyl hydroxamic acids.
Synthetic inhibitors of interstitial collagenase, tri- and tetrapeptidyl hydroxamic acids, have been developed and tested for their inhibitory activities against human matrix metalloproteinases. A water soluble inhibitor, p-NH2-Bz-Gly-Pro-D-Leu-D-Ala-NHOH (FN-439) inhibited interstitial and granulocyte collagenases, granulocyte gelatinase and skin fibroblast stromelysin with IC50 of 1 x 10(-6) M, 3.0 x 10(-5) M and 1.5 x 10(-4), respectively, but not thermolysin and serine proteinases. FN-439 was found to retain its inhibitory activity against matrix metalloproteinases even after prolonged incubation with pronase or human granulocyte elastase, indicating a favorite candidate of the inhibitor to modulate metalloproteinase activities in vivo.
Odake
S
S
Research Institute, Fuji Chemical Ind. Ltd., Toyama, Japan.
Morita
Y
Y
Morikawa
T
T
Yoshida
N
N
Hori
H
H
Nagai
Y
Y
D000595:Amino Acid Sequence; D005347:Fibroblasts / Q000201:enzymology; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000097:blood; D006098:Granulocytes / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007700:Kinetics; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012867:Skin / Q000201:enzymology; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3