文献类型：期刊文献

英文题名：A highly active angiotensin I-converting enzyme inhibitory peptide KAKW designed based on the role of C-terminal residue, and its antihypertensive effects on spontaneously hypertensive rats

作者：Hu, Yangting[1];Xie, Dewei[1];Chen, Xujun[1];Li, Peng[1];Zhao, Li[1];Gao, Bei[1];Du, Lei[1];Xie, Jingli[1,2]

机构：[1]East China Univ Sci & Technol, Sch Biotechnol, Dept Food Sci & Engn, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Shanghai Collaborat Innovat Ctr Biomfg SCICB, Shanghai 200237, Peoples R China

年份：2025

卷号：290

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001459536700001)】；

基金：This work was supported by the National Key Research and Devel-opment Program of China (Nos. 2020YFA0907800) , China. The authors thank Research Center of Analysis and Test of East China University of Science and Technology for the help on the characterization.

语种：英文

外文关键词：ACE inhibitory peptide; Pistachio; Molecular docking; C -terminus design; Structure-activity relationship; Antihypertension

摘要：Angiotensin converting enzyme (ACE) inhibitory peptide KAKP with IC50 of 7.23 +/- 0.30 mu M was identified from trypsin hydrolysate of pistachio (Pistacia vera L.) through multiple purifications. A series of peptides were designed based on KAKP to reveal the role of the C-terminal residue in the ACE inhibition, including KAK-Xaa (hydrophobic residue), KAK and KAPK. The designed peptide KAKW exhibited a superior ACE inhibitory effect with IC50 of 2.02 +/- 0.20 mu M. Molecular docking discovered that the hydrophobic C-terminal residues with ring structure facilitated the interaction with Zn2+ and it-it interactions within the ACE active pocket. Isothermal titration calorimetry revealed that the thermodynamic property of KAKW was enthalpy-driven with a lower Kd (57.7 nM) than KAKP (141 nM). KAKW could decrease 20 mmHg SBP at 4 h and 18 mmHg DBP at 6 h during the acute trial of spontaneously hypertensive rats (SHRs), compared to that Lisinopril dropped 33 mmHg SBP and 28 mmHg DBP at 2 h. After a subacute administration of KAKW for 4 w, the strong inhibition of 61.6 % serum ACE activity and the reduction of 33.3 % angiotensin II level were achieved. Although KAKW was less potent than Lisinopril, it provided a more moderate and sustained reduction in blood pressure, beneficial for long-term hypertension management. Meanwhile, KAKW ameliorated gut microbiota dysbiosis in SHRs and increased the levels of fecal short-chain fatty acids, demonstrating advantages over Lisinopril in modulating gut microbiota. This work provides a novel scheme for structure-activity study and a prospective candidate for hypertension management.