Citrullyl-Hydroxyprolyl-Proline (ChPP): An Artificially Synthesized Tripeptide as Potent ACE Inhibitor
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Citrullyl‑Hydroxyprolyl‑Proline (ChPP): An Artificially Synthesized Tripeptide as Potent ACE Inhibitor Bingjun Qian1 · Lili Yu1 · Chongchong Tian1 · Siyi Huang1 · Jianghua Huo1 · Oscar D. Villarreal2 Received: 5 July 2020 / Revised: 2 November 2020 / Accepted: 16 November 2020 © Springer Nature B.V. 2020
Abstract Currently bioactive peptides are the main focus in attempts to identify novel angiotensin-converting enzyme inhibitors (ACEIs) for the treatment of hypertension due to their fewer side effects. In the present study we aimed to investigate the antihypertensive activity of 4 synthetic tripeptides Ornithyl-Hydroxyprolyl-Proline (Orn-Hyp-Pro OhPP) Ornithyl-ProlylHydroxyproline (Orn-Pro-Hyp OPhP) Citrullyl-Hydroxyprolyl-Proline (Cit-Hyp-Pro ChPP) and Citrullyl-Prolyl-Hydroxyproline (Cit-Pro-Hyp CPhP) in vitro and in vivo. The ACE inhibitory activity and mode were analyzed with a modified spectrophotometric method and Lineweaver-Burk plots respectively. It showed that peptide Citn-Hyp-Pro (ChPP) exhibited the highest inhibition potency with an IC50 value of 40.48 μM and displayed a competitive inhibition of ACE. Molecular docking simulations suggested that ChPP could form several critical hydrogen bonds with the major residues His353 and His513 located in the S2 active site of ACE. The systolic blood pressure of spontaneously hypertensive rats monitored by the tail-cuff method was significantly reduced by 15.54% at 4 h after oral administration of 20 mg/kg BW ChPP. Also ChPP remarkably downregulated the angiotensin II receptor type 1 (agtr1) and miR-132/-212 levels in SHRs which was similar to that observed in SHRs treated with captopril. It showed us that the tripeptide ChPP could be explored as a promising ACE inhibitor (ACEI) for treatment of hypertension. Keywords Peptide design · Tripeptide ChPP · Molecular docking · Antihypertensive activity · Transcriptional regulation · agtr1 · miR-132-212
Introduction Hypertension (HT), characterized by elevated systemic blood pressure (BP), is one of the most common chronic diseases that affects over one billion people worldwide (Mills et al. 2016). It is a major risk factor for cardiovascular disease (CVD). Angiotensin-I converting enzyme (ACE EC3.4.15.1), a zinc-containing dipeptidase, plays an important role in the regulation of BP by catalyzing the Bingjun Qian, Lili Yu and Chongchong Tian contributed equally to this work. * Bingjun Qian [email protected] 1
Department of Preventive Medicine Biomedical Research Institute, Jiangsu Vocational College of Medicine, Jiangsu 224005, People’s Republic of China
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 77030, USA
2
cleavage of angiotensin-I (Ang I) to the potent vasopressor angiotensin-II (Ang II) (Hayes et al. 2016) and the degradation of the vasodilator bradykinin (Regoli and Gobeil 2015). Consequently, ACE is considered as a therapeutic target for the treatment of HT. Apart from the direct vasoconstriction, Ang II is also a
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