Arachin derived peptides as selective angiotensin I-converting enzyme (ACE) inhibitors: structure-activity relationship.

Current attention focuses on mechanisms of controlling blood pressure through the inhibition of angiotensin I-converting enzyme (ACE). Bioactive antihypertensive peptides of food origin are increasingly gaining importance as alternates to synthetic drugs in hypertension therapy. The ACE inhibitory property of an enzymatic digest of arachin, the major storage globulin of peanut (Arachis hypogaea) has been demonstrated. The ACE inhibitory activity of a tripeptide (IEY) isolated from these digests has been characterized. Five synthetic structural analogs of this peptide (IEW, IKY, IKW, IEP and IKP) were assembled and their ACE inhibitory activity evaluated. Among these, the tripeptide IKP was a potent competitive inhibitor with an IC(50) of 7+/-1 x 10(-6)M similar to that of the potent whey peptides IPP and VPP. The inhibition data of these peptide analogs have been rationalized through docking simulations using the tACE-lisinopril complex at 2A resolution (PDB: 1086). The best docking poses were located at the tACE catalytic site resembling the mode of inhibition exerted by lisinopril, the synthetic drug. The degree of inhibition by the peptides correlated with the coordination distance between the catalytic Zn(II) and the carbonyl oxygen of the peptide bond between the amino-terminal and middle residue. These studies illustrate that these peptides, like lisinopril, behave as transition state analog inhibitors and are useful in therapeutic intervention for blood pressure management. Copyright 2010 Elsevier Inc. All rights reserved.