Inhibition of adamalysin II and MMPs by phosphonate analogues of snake venom peptides

Phosphonate analogues of the peptidomimetic N-(Furan-2-yl)carbonyl-Leu-Trp- OH were prepared with the goal of evaluating the effect of phosphonate for carboxylate replacement on binding with snake venom metalloproteinases and MMPs, N(Furan-2-yl)carbonyl-Leu-L-Trp(P)-(OH)(2) showed a 75-fold increase of the inhibiting activity against adamalysin II, a snake venom metalloprot einase structurally related to MMPs and TACE. Both the phosphonate and carb oxylate peptidomimetics fit into the active site adopting a retrobinding mo de and provide the structural base for a new class of metalloproteinases in hibitors. (C) 1999 Elsevier Science Ltd. All rights reserved.