title: New thiol inhibitors of Clostridium histolyticum collagenase. Importance of the P3' position.
abstract: An extensive series of synthetic mercaptotripeptides (HS-CH2-CH2-CO-Pro-Yaa) was prepared, and the inhibitory constants were determined on the Clostridium histolyticum collagenase. Among the factors which control the optimal binding of these inhibitors, we found that the presence of a free C-terminal carboxylate group in the position P3' of the compounds is of primary importance. In general, the esterification of this carboxylate group decreased the potency of the inhibitors by two orders of magnitude. We observed also that the enzyme favored the inhibitors having a long linear apolar or basic side-chain at the position P3'. The present data suggest a large S3' subsite of the C. histolyticum collagenase. The compound which contains a homoarginine residue at the P3' position with a Ki of 0.2 microM proved to be the most potent synthetic inhibitor known to date for the C. histolyticum collagenase.
authors.affiliation: Laboratory of Organic Chemistry, University of Athens.
authors.forename: A
authors.initials: A
authors.lastname: Yiotakis
authors.forename: A
authors.initials: A
authors.lastname: Hatgiyannacou
authors.forename: V
authors.initials: V
authors.lastname: Dive
authors.forename: F
authors.initials: F
authors.lastname: Toma
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D003013:Clostridium / Q000201:enzymology*; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
chemical_list: D009842:Oligopeptides; D013438:Sulfhydryl Compounds; D003012:Microbial Collagenase