title: Structure-based design and optimization of antihypertensive peptides to obtain high inhibitory potency against both renin and angiotensin I-converting enzyme.
abstract: The human renin-angiotensin system (RAS) plays an essential role in regulating blood pressure and systemic vascular resistance. Renin and angiotensin I-converting enzyme (ACE) are two key enzymes in RAS and have long been recognized as attractive antihypertensive targets. Here, a synthetic strategy was proposed integrating quantitative structure-activity relationship (QSAR), molecular dynamics (MD) simulation and binding free energy analysis to discover novel dual renin and ACE peptidic inhibitors. With the strategy a number of candidates were generated virtually, from which eight promising peptides were selected and synthesized for biological assay. Consequently, three peptides (RYLP, YTAWVP and YRAWVL) were successfully identified to have satisfactory inhibitory profile against both renin and ACE with IC50values of <1 mM and <10 μM, respectively. Structural analysis and energetic dissection revealed different binding modes of peptide to renin and ACE; a peptide only inserts its C-terminus into the active site of ACE, whereas the whole peptide packs tightly against renin. In addition, when limited to structural diversity it is hard to reconcile the renin and ACE inhibitory activities of short peptides such as dipeptides. These findings can be used to guide peptide optimization with improved biological activity.
authors.affiliation: a Department of Cardiology , Jiujiang No.1 People's Hospital of Jiangxi Province , Jiujiang , China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: b Department of Cardiothoracic Surgery , Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China.
authors.forename: C
authors.initials: C
authors.lastname: Cheng
authors.affiliation: c Department of Internal Medicine , Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
keywords: angiotensin I-converting enzyme; cardiovascular disease; hypertension; peptide; quantitative structure–activity relationship; renin