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.