Modulating the cardiovascular pharmacology of apelin and elabela peptide by structural constraints
Kien Tran
Postdoctoral Fellow, Universite de Montreal
Apelin receptor (APJ) belongs to the class A G-proteins coupled receptor (GPCR) and plays a major role in cardiovascular functions. Recently, small molecules targeting APJ have entered clinical stages for the treatment of heart failure and muscular aging. Those small molecules bring the treatment closer than ever to the patient, but this is made possible only by a deep understanding of the underlying pharmacology which was gained through decades of studies using peptides as an experimental tool. Apelin and elabela are two endogenous ligands of the apelin receptor. By using different methods of structural modification, such as macrocyclization, substitution by unnatural and constrained amino acids, we elucidated key binding elements of those endogenous peptides. We compared them and used this knowledge to improve the affinity, the drug like properties as well as diversified their signaling profile. Several modified analogs have lower molecule weight compared to apelin-13 but significant longer half-life (t1/2 in vivo up to 3.7 h vs apelin-13, t1/2 < 1 min in Sprague-Dawley rat) and produce sustained cardiac effects.
Kien TRAN earned his PhD in Pharmacology at the Université de Sherbrooke, Canada and he is currently a postdoctoral fellow at the Institute for Research in Immunology and Cancer, Université de Montreal. The main theme of his work consists of developing macrocyclic ligands for challenging targets such as peptide-binding GPCR (apelin receptor) or protein-protein interaction interface (oncogenic Ras).