Discovery and Structure–Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions
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- 作者：Alexandre Murza ; Xavier Sainsily ; David Coquerel ; Jérôme Côté ; Patricia Marx ; Élie Besserer-Offroy ; Jean-Michel Longpré ; Jean Lainé ; Bruno Reversade ; Dany Salvail ; Richard Leduc ; Robert Dumaine ; Olivier Lesur ; Mannix Auger-Messier ; Philippe Sarret ; Éric Marsault
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：April 14, 2016
- 年：2016
- 卷：59
- 期：7
- 页码：2962-2972
- 全文大小：496K
- 年卷期：0
- ISSN：1520-4804
文摘
ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA’s structure–activity relationships and report the identification of analogue 3 (ELA(19–32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.