217082-60-5Relevant articles and documents
Linking (Pyr)1apelin-13 pharmacokinetics to efficacy: Stabilization and measurement of a high clearance peptide in rodents
Onorato, Joelle M.,Xu, Carrie,Chen, Xue-Qing,Rose, Anne V.,Generaux, Claudia,Lentz, Kimberley,Shipkova, Petia,Arthur, Susan,Hennan, James K.,Haskell, Roy,Myers, Michael C.,Lawrence, R. Michael,Finlay, Heather J.,Basso, Michael,Bostwick, Jeffrey,Fernando, Gayani,Garcia, Ricardo,Hellings, Samuel,Hsu, Mei-Yin,Zhang, Rongan,Zhao, Lei,Gargalovic, Peter
, p. 41 - 50 (2019)
Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.
Identifying structural determinants of potency for analogs of apelin-13: Integration of C-terminal truncation with structure-activity
Zhang, Yanyan,Maitra, Rangan,Harris, Danni L.,Dhungana, Suraj,Snyder, Rodney,Runyon, Scott P.
, p. 2992 - 2997 (2014/05/20)
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.
