INHIBITION OF MATRIX METALLOPROTEINASES BY PEPTIDYL HYDROXAMIC ACIDS

Synthetic inhibitors of interstitial collagenase, tri- and tetrapeptid yl hydroxamic acids, have been developed and tested for their inhibito ry activities against human matrix metalloproteinases. A water soluble inhibitor, p-NH2-Bz-Gly-Pro-D-Leu-D-Ala-NHOH (FN-439) inhibited inter stitial 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) M, respectively, but not thermolysin and serine proteinase s. FN-439 was found to retain its inhibitory activity against matrix m etalloproteinases even after prolonged incubation with pronase or huma n granulocyte elastase, indicating a favorite candidate of the inhibit or to modulate metalloproteinase activities in vivo. (C) 1994 Academic Press, Inc.