Current Inhibition Concepts of Zinc Metallopeptidases Involved in Blood Pressure Regulation

Certain Zinc Metallopeptidases, such as Angiotensin Converting Enzyme (ACE), Neutral Endopeptidase (NEP) and Endothelin Converting Enzyme (ECE), play a key role in vascular homeostasis through their proteolytic activity in various vasoactive peptides. Effective inhibitors for these enzymes were until recently designed in the absence of the X-ray structure of these enzymes, and a variety of ACE inhibitors are commercially available. A new class of promising compounds, namely vasopeptidase inhibitors, have emerged and they represent a new concept in hypertension and cardiovascular disease therapeutics. They contemporarily inhibit the catalytic function of more than one of the above enzymes and they are undergoing extensive clinical trials exhibiting increased efficacy in hypertension treatment and higher risk for side effects such as angioedema when compared to ACE inhibitors. The determination of the substrate-free and substrateloaded X-ray models of NEP and ACE provides valuable insight of the structure determinants in enzymesubstrate interaction and it is believed that new more selective inhibitors could be afforded through structurebased drug design process. Selectivity towards target enzyme even in simultaneous inhibition could modify the breakdown of vasodilator and vasoconstrictor peptides and could therefore modulate the balance of the risk-benefit profile.