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Active-site directed peptide L-Phe-D-His-L-Leu inhibits angiotensin converting enzyme activity and dexamethasone-induced hypertension in rats.

Peptides 2018 November 25
Hypertension is the fundamental cause of cardiovascular and cerebrovascular disorders. Several natural and synthetic peptides are being used as anti-hypertensive 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 IC50 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 anti-hypertensive drugs.

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