Inhibition of Zinc Metallopeptidases in Cardiovascular Disease - From Unity to Trinity, or Duality?

被引:32
作者
Dive, Vincent [3 ]
Chang, Cheng-Fu [1 ,2 ]
Yiotakis, Athanasios [4 ]
Sturrock, Edward D. [1 ,2 ]
机构
[1] Univ Cape Town, Div Med Biochem, ZA-7925 Observatory, South Africa
[2] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Observatory, South Africa
[3] CE Saclay Gif Yvette, iBiTecS, SIMOPRO, CEA, F-91191 Gif Sur Yvette, France
[4] Univ Athens, Organ Chem Lab, Dept Organ Chem, GR-15771 Athens, Greece
基金
英国惠康基金; 新加坡国家研究基金会;
关键词
Angiotensin-converting enzyme; neutral endopeptidase; endothelin converting enzyme; ACE2; cardiovascular disease; vasopepidase inhibitor;
D O I
10.2174/138161209789271889
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The fusion of therapeutics and diagnostic medicine in an effort to provide individualized pharmacotherapy frequently requires the manipulation of drugs that target different enzymes and receptors. To this end, and as a strategy to increase the efficiency of drug development pipelines, new chemical entities are often developed that interact with more than one target. Angiotensin-converting enzyme (ACE), its homologue ACE2, neutral endopeptidase (NEP) and endothelin-converting enzyme (ECE-1) are metallopeptidases that are involved in the metabolism of biologically active peptides that impact on the regulation of the cardiovascular system. The benefit of the ACE/NEP; NEP/ECE and ACE/NEP/ECE dual and triple inhibitors is not only their possible increased efficacy with respect to blood pressure control, but also their other activities, such as antiproliferative, anti-fibrotic and anti-inflammatory, mediated by angiotensin II and atrial natriuretic peptide. Over the last few years a number of three-dimensional structures of these metallopeptidases have advanced our understanding of the mode of interaction between various ligands and their target binding sites. This information is invaluable in the rational design of new and improved drugs. Here we review the structural basis for the design of single and multiple metallopeptidase inhibitors for the treatment of cardiovascular disease. Moreover, we present recent advances in the development of ACE/ECE-1 inhibitors that are likely to have high potency and improved side effect profiles.
引用
收藏
页码:3606 / 3621
页数:16
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