Inhibition of Human Stromelysin by Peptides Based on the N-Terminal Domain of Tissue Inhibitor of Metalloproteinases-1

Abstract

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], (IC 50, 42 μM). 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.