title: Vertebrate collagenase inhibitor. II. Tetrapeptidyl hydroxamic acids.
abstract: To develop a potent and specific collagenase inhibitor, a series of tetrapeptidyl hydroxamic acids were synthesized, based on the previous findings with tripeptidyl derivatives (Chem. Pharm. Bull., 38, 1007-1011, 1990). Among the series of tetrapeptidyl derivatives synthesized, R-Gly-Pro-Leu-Ala-NHOH and R-Gly-Pro-D-Leu-D-Ala-NHOH were found to be highly specific and potent inhibitors against vertebrate collagenase with an IC50 of 10(-6) M order, where R stands for Boc or acyl group. Analysis of their structure-activity relationships showed a characteristic feature of the substrate-binding site of collagenase as follows: 1) the S1 subsite forms a shallow hydrophobic pocket, although glycine residue corresponds to the subsite of the natural collagen substrate: 2) the S2 subsite constitutes a bulky pocket with less requirement for hydrophobicity: 3) the S3 subsite preferentially accommodates Pro residue: and 4) the accommodation of the P4-P1 subsites of peptidyl collagenase inhibitor to the S4-S1 subsites is required to form a tight binding of its hydroxamic acid moiety to the zinc ion at the catalytic site of the enzyme. The introduction of an enantiometric dipeptide unit, D-Leu-D-Ala, to the P2-P1 subsites demonstrated an increased binding capacity to the extended S4-S1 subsites of collagenase, thus providing proteinase-resistant inhibitor.
authors.affiliation: Research Institute, Fuji Chemical Industries, Ltd., Toyama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Odake
authors.forename: T
authors.initials: T
authors.lastname: Okayama
authors.forename: M
authors.initials: M
authors.lastname: Obata
authors.forename: T
authors.initials: T
authors.lastname: Morikawa
authors.forename: S
authors.initials: S
authors.lastname: Hattori
authors.forename: H
authors.initials: H
authors.lastname: Hori
authors.forename: Y
authors.initials: Y
authors.lastname: Nagai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001001:Anura; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D009842:Oligopeptides; D003012:Microbial Collagenase