Active-site Directed Peptide L-Phe-d-His-l-Leu Inhibits Angiotensin Converting Enzyme Activity and Dexamethasone-induced Hypertension in Rats

Hypertension is the fundamental cause of cardiovascular and cerebrovascular disorders. Several natural and synthetic peptides are being used as antihypertensive agents, which target angiotensin converting enzyme (ACE), the master regulator of angiotensin (Ang) II production. In this study, we have evaluated ACE-inhibitory potential of the tripeptide l-Phenylalanyl-d-Histidyl-l-Leucine (l-Phe-d-His-l-Leu) in vitro and its antihypertensive effect in rat model of dexamethasone-induced hypertension. l-Phe-d-His-l-Leu was custom-designed by changing the configuration of penultimate amino acid residue (histidine) from C-terminal of Ang I, the site at which ACE acts upon and generates Ang II. l-Phe-d-His-l-Leu effectively inhibited ACE activity in a dose-dependent and competitive manner with an IC of 53.32 ± 0.13 nmol/L. Both fluorescence spectra and circular dichroism data revealed the direct interaction between l-Phe-d-His-l-Leu and ACE. In addition, molecular docking studies revealed the strong interaction of l-Phe-d-His-l-Leu with the critical active site amino acid residues of ACE. Further, the administration of l-Phe-d-His-l-Leu resulted in decrease in blood pressure (142 ± 3 mmHg) compared to dexamethasone alone group (167 ± 2 mmHg). Besides, l-Phe-d-His-l-Leu decreased the levels of circulating Ang II, and reduced fibrosis in heart and kidney, as evidenced by decreases in collagen deposition. Thus, the strategy of incorporation of d-amino acids in ACE-inhibitory peptides could be valuable in the development of antihypertensive drugs.