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

  • J Med Chem. 2016 Apr 14;59(7):2962-72. doi: 10.1021/acs.jmedchem.5b01549.
Alexandre Murza  1  2 ,  Xavier Sainsily  1  2 ,  David Coquerel  3 ,  Jérôme Côté  1  2 ,  Patricia Marx  1  2 ,  Élie Besserer-Offroy  1  2 ,  Jean-Michel Longpré  1  2 ,  Jean Lainé  1 ,  Bruno Reversade  4 ,  Dany Salvail  5 ,  Richard Leduc  1  2 ,  Robert Dumaine  1 ,  Olivier Lesur  3 ,  Mannix Auger-Messier  3 ,  Philippe Sarret  1  2 ,  Éric Marsault  1  2
Affiliations
  • 1. Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
  • 2. Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
  • 3. Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
  • 4. Laboratory of Human Embryology & Genetics, Institute of Medical Biology, A*STAR , 8A Biomedical Grove, 138648 Singapore.
  • 5. IPS Thérapeutique Inc. , Sherbrooke, J1G 5J6 Québec, Canada.
PMID: 26986036 DOI: 10.1021/acs.jmedchem.5b01549
Abstract

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.

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