2. Academic Validation
  3. Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions

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

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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