INHIBITION OF HUMAN STROMELYSIN BY PEPTIDES BASED ON THE N-TERMINAL DOMAIN OF TISSUE INHIBITOR OF METALLOPROTEINASES-1

The tissue inhibitors of metalloproteinases (TIMPs) represent a family of naturally occurring protein inhibitors of stromelysin and other members of the family of matrix metalloproteinases. A series of peptides based on the N-terminal sequence of natural TIMP-1 was synthesized and assessed for inhibitory activity against purified human stromelysin. Inhibitor peptides were identified in the loop (bounded by the disulfide bonds [C-3-C-99] and [C-13-C-124]), e.g., [C-3(Acm)-C-13], (IC50, 42 mu M). It was established that inhibition was due to the free sulfhydryl group of either C-13 or C-124. However, peptides within [C-70(Acm)-C-98(Acm)] inhibited stromelysin independently of zinc co-ordination by cysteine. The binding epitope in TIMP-1 may be discontinuous and comprised of sequences from at least 2 loops. (C) 1994 Academic Press, Inc.