Matrix metalloproteinase‐2 inhibition by temocapril and its important role in peritoneal transport

D Yamamoto, S Takai, T Akimoto… - Clinical and …, 2012 - Wiley Online Library
D Yamamoto, S Takai, T Akimoto, I Hirahara, C Ito, S Muto, E Kusano
Clinical and Experimental Pharmacology and Physiology, 2012Wiley Online Library
Summary 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. 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 …
Summary
  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 (IC50 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.
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