title: C-Terminal modifications of apelin-13 significantly change ligand binding, receptor signaling, and hypotensive action.
abstract: Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor family. This system plays an important role in the regulation of blood pressure and cardiovascular functions. To better understand the role of its C-terminal Phe(13) residue on ligand binding, receptor signaling, and hypotension, we report a series of modified analogues in which Phe(13) was substituted by unnatural amino acids. These modifications delivered new compounds exhibiting higher affinity and potency to inhibit cAMP accumulation compared to apelin-13. In particular, analogues Bpa(13) or (α-Me)Phe(13) were 30-fold more potent to inhibit cAMP accumulation than apelin-13. Tyr(OBn)(13) substitution led to a 60-fold improvement in binding affinity and induced stronger and more sustained drop in blood pressure compared to apelin-13. Our study identified new potent analogues of apelin-13, which represent valuable probes to better understand its structure-function relationship.
authors: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec Canada.
authors: Alexandre
authors: A
authors: Murza
authors: Élie
authors: É
authors: Besserer-Offroy
authors: Jérôme
authors: J
authors: Côté
authors: Patrick
authors: P
authors: Bérubé
authors: Jean-Michel
authors: JM
authors: Longpré
authors: Robert
authors: R
authors: Dumaine
authors: Olivier
authors: O
authors: Lesur
authors: Mannix
authors: M
authors: Auger-Messier
authors: Richard
authors: R
authors: Leduc
authors: Philippe
authors: P
authors: Sarret
authors: Éric
authors: É
authors: Marsault
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000073861:Apelin; D001794:Blood Pressure / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D007022:Hypotension / Q000188:drug therapy*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000073861:Apelin; C498579:Apln protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide; D000242:Cyclic AMP