Elucidation of the structure-activity relationships of apelin: influence of unnatural amino acids on binding, signaling, and plasma stability.

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.