Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions

作者：Murza Alexandre; Sainsily Xavier; Coquerel David; Cote Jerome; Marx Patricia; Besserer Offroy Elie; Longpre Jean Michel; Laine Jean; Reversade Bruno; Salvail Dany; Leduc Richard; Dumaine Robert; Lesur Olivier; Auger Messier Mannix; Sarret Philippe; Marsault Eric^*

来源：Journal of Medicinal Chemistry, 2016, 59(7): 2962-2972.

DOI：10.1021/acs.jmedchem.5b01549

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 G alpha(i1) and beta-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.

• 出版日期2016-4-14
• 单位河北医科大学