title: Identifying structural determinants of potency for analogs of apelin-13: integration of C-terminal truncation with structure-activity.
abstract: 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.
authors.affiliation: Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
authors.affiliation: Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Danni L
authors.initials: DL
authors.lastname: Harris
authors.affiliation: Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Suraj
authors.initials: S
authors.lastname: Dhungana
authors.affiliation: Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Rodney
authors.initials: R
authors.lastname: Snyder
authors.affiliation: Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709, United States. Electronic address: srynyon@rti.org.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D036341:Intercellular Signaling Peptides and Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C495199:apelin-13 peptide
keywords: APJ; Agonist; Apelin; Function; Peptide; Structure–activity; Truncation