Vertebrate Collagenase Inhibitor. II. Tetrapeptidyl Hydroxamic Acids

概要

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To develop a potent and specific collagenas inhibitor, a series of tetrapheptidyl 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 IC_<50> 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 S_1 subsite forms a shallow hydrophobic pocket, although glycine residue corresponds to the subsite of the natural collagen substrate : 2) the S_2 substite constitutes a bulky pocket with less requirement for hydrophobicity : 3) the S_3 subsitte preferentially accommodates Pro residue : and 4) the accommodation of the P_4-P_1 substites of peptidyl collagenase inhibitor to the S_4-S_1 substites 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 P_2-P_1 subsites demonstrated an increased binding capacity to the extended S_4-S_1 subsites of collagenase, thus providing proteinase-resistant inhibitor.
社団法人日本薬学会の論文
1991-06-25