title: Matrix metalloproteinase-2 inhibition by temocapril and its important role in peritoneal transport.
abstract: 1. Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis (PD), but MMP-2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin-converting enzyme inhibitor (ACEI), can inhibit MMP-2. 2. To investigate the potential usefulness of ACEI during PD, the molecular interaction between the MMP-2 active site and the active form of temocapril (temocaprilat) was investigated using molecular modelling. Furthermore, the effects of temocapril on MMP-2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. 3. Temocaprilat bound to the MMP-2 active centre and recognized two hydrophobic substrate-binding sites in the MMP-2 molecular model. Matrix metalloproteinase-2 activity in peritoneal effluents was directly inhibited by temocaprilat (IC(50) 0.47 μmol/L). In one patient given temocapril, the peritoneal solute transport rate decreased gradually during PD. 4. Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP-2 inhibition to prevent peritoneal injury caused by PD.
authors.affiliation: Biomedical Computation Center, Osaka Medical College, Osaka, Japan. center@art.osaka-med.ac.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akimoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hirahara
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ito
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
mesh_terms: D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D020134:Catalytic Domain; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008875:Middle Aged; D010530:Peritoneal Dialysis / Q000379:methods*; D017434:Protein Structure, Tertiary; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013841:Thiazepines; C055603:temocapril hydrochloride; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2