Inhibition of human skin fibroblast collagenase by phosphorus-containing peptides.
Substitution of the phosphonamidate linkage (PO2-NH) for the peptide bond (CO-NH) in substrate-like sequences produces inhibitors of human skin fibroblast collagenase with Ki's far below Km for the native collagen substrate. Using a thiol ester substrate at pH 6.5, phthaloyl-GlyP-Ile-Trp-(S)NHCH-(Me)Ph, the phosphonamidate analog of phthaloyl-Gly-Ile-Trp-(S)NHCH(Me)Ph, has a Ki of 20 nM. Peptide phosphonamidates with amino acid sequences extended further to the right or the left of the Gly-Ile-Trp sequence had higher Ki's. Substitution of the phosphinate linkage (PO2-CH2) for the peptide bond also gives potent inhibitors such as napthoyl-GlyP-C-Leu-Trp-NHBzl, the phosphinate analog of naphtholyl-Gly-Leu-Trp-NHBzl, which has a Ki of 10 nM. Some of the phosphonamidates and phosphinates are also excellent inhibitors of the bacterial zinc metalloproteases thermolysin and Pseudomonas aeruginosa elastase.
Galardy
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University of Kentucky, Lexington 40536.
Grobelny
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D
Kortylewicz
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ZP
Poncz
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L
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D012867:Skin / Q000166:cytology; D013329:Structure-Activity Relationship; D013820:Thermolysin / Q000037:antagonists & inhibitors
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D008666:Metalloendopeptidases; C043859:pseudolysin, Pseudomonas aeruginosa; D013820:Thermolysin