Peptides based on the conserved predomain sequence of matrix metalloproteinases inhibit human stromelysin and collagenase.
Prostromelysin, a member of the family of matrix metalloproteinases, is secreted as a zymogen which is activated after cleavage of the His81-Phe82 bond. The 82 amino acid propeptide that is removed during activation contains 12 amino acids, MRKPRC75GVPDVG, that are highly conserved in all MMPs. We evaluated a series of peptides that span this region for their ability to inhibit stromelysin. The hexapeptide, Ac-RCGVPD, and the pentapeptide, Ac-RCGVP had IC50 values of approx. 10 microM. The tetrapeptide, Ac-RCGV, was somewhat less potent with an IC50 of 60 microM. Smaller peptides, e.g. Ac-RCG, were significantly less potent as inhibitors. Substitutions of Cys75 with Ser resulted in a complete loss of inhibitory activity. The peptides in this series also inhibited human fibroblast collagenase.
Hanglow
A C
AC
Department of Arthritis Research, Hoffmann-La Roche, Nutley, NJ 07110.
Lugo
A
A
Walsky
R
R
Finch-Arietta
M
M
Lusch
L
L
Visnick
M
M
Fotouhi
N
N
D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry; D004792:Enzyme Precursors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*
D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D008666:Metalloendopeptidases; C048047:prostromelysin; D019278:Matrix Metalloproteinase 3; D003545:Cysteine