Discovery and Structure Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions.
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 Gai1 and b 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.
Journal of medicinal chemistry