title: Elucidation of the structure-activity relationships of apelin: influence of unnatural amino acids on binding, signaling, and plasma stability.
abstract: Apelin is the endogenous ligand of the APJ receptor, a member of the G-protein-coupled receptor family. The apelin-APJ complex has been detected in many tissues and is emerging as a promising target for several pathophysiological conditions. There is currently little information on the structure-activity relationship (SAR) of the apelin hormone. In an effort to better delineate SAR, we synthesized analogues of apelin-13 modified at selected positions with unnatural amino acids, with a particular emphasis on the C-terminal portion. Analogues were then tested in binding and functional assays by evaluating Gi/o-mediated decreases in cAMP levels and by assessing β-arrestin2 recruitment to the APJ receptor. The plasma stability of new compounds was also assessed. Several analogues were found to possess increased binding and higher stability than the parent peptide.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12eAvenue Nord, Sherbrooke, QC, J1H 5N4, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Murza
authors.forename: Alexandre
authors.initials: A
authors.lastname: Parent
authors.forename: Elie
authors.initials: E
authors.lastname: Besserer-Offroy
authors.forename: Hugo
authors.initials: H
authors.lastname: Tremblay
authors.forename: Félix
authors.initials: F
authors.lastname: Karadereye
authors.forename: Nicolas
authors.initials: N
authors.lastname: Beaudet
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000075244:Apelin Receptors; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D055550:Protein Stability; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: C104575:APLNR protein, human; D000596:Amino Acids; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide; D000242:Cyclic AMP