Elucidation of the Structure-Activity Relationships of Apelin: Influence of Unnatural Amino Acids on Binding, Signaling, and Plasma Stability

作者：Murza Alexandre; Parent Alexandre; Besserer Offroy Elie; Tremblay Hugo; Karadereye Felix; Beaudet Nicolas; Leduc Richard; Sarret Philippe; Marsault Eric^*

来源：ChemMedChem, 2012, 7(2): 318-325.

DOI：10.1002/cmdc.201100492

• apelin
• plasma stability
• receptors
• signaling
• structure-activity relationships

Apelin is the endogenous ligand of the APJ receptor, a member of the G-protein-coupled receptor family. The apelinAPJ 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 structureactivity 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 beta-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.

• 出版日期2012-2-6