Identifying structural determinants of potency for analogs of apelin-13: Integration of C-terminal truncation with structure-activity

Apelin peptides function as endogenous ligands of the APJ receptor and have been implicated in a number of important biological processes. While several apelinergic peptides have been reported, apelin-13 (Glu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe) remains the most commonly studied and reported ligand of APJ. This study examines the effect of C-terminal peptide truncations and comprehensive structure-activity relationship (SAR) for a series of analogs based on apelin-13 in an attempt to develop more potent and stable analogs. C-terminal truncation studies identified apelin-13 (N-acetyl 2-11) amide (9) as a potent agonist (EC50 = 4.4 nM). Comprehensive SAR studies also determined that Arg-2, Leu-5, Lys-8, Met-11, were key positions for determining agonist potency, whereas the hydrophobic volume of Lys-8 was a specific determinate of activity. Plasma stability studies on the truncated 10-mer peptide 28 (EC50 = 33 nM) indicated the primary sites of cleavage occurred between Nle-3 and Leu-4 and also between Ala-5 and Ala-6. These new ligands represent the shortest known apelin peptides with good functional potency. (C) 2014 Elsevier Ltd. All rights reserved

Zhang, Y. Y., Maitra, R., Harris, D., Dhungana, S., Snyder, R., & Runyon, S. (2014). Identifying structural determinants of potency for analogs of apelin-13: Integration of C-terminal truncation with structure-activity. Bioorganic and Medicinal Chemistry, 22(11), 2992-2997. DOI: 10.1016/j.bmc.2014.04.001