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 [C3-C99] and [C13-C124]), e.g., [C3(Acm)-C13], (IC50, 42 microM). It was established that inhibition was due to the free sulfhydryl group of either C13 or C124. However, peptides within [C70(Acm)-C98(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.
Hanglow
A C
AC
Department of Inflammation, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Lugo
A
A
Walsky
R
R
Visnick
M
M
Coffey
J W
JW
Fotouhi
N
N
D000595:Amino Acid Sequence; D006023:Glycoproteins / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D019714:Tissue Inhibitor of Metalloproteinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3