C‑Terminal Modifications of Apelin-13 Significantly Change Ligand Binding, Receptor Signaling, and Hypotensive Action

Abstract

Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor family. This system plays an important role in the regulation of blood pressure and cardiovascular functions. To better understand the role of its C-terminal Phe¹³ residue on ligand binding, receptor signaling, and hypotension, we report a series of modified analogues in which Phe¹³ was substituted by unnatural amino acids. These modifications delivered new compounds exhibiting higher affinity and potency to inhibit cAMP accumulation compared to apelin-13. In particular, analogues Bpa¹³ or (α-Me)­Phe¹³ were 30-fold more potent to inhibit cAMP accumulation than apelin-13. Tyr­(OBn)¹³ substitution led to a 60-fold improvement in binding affinity and induced stronger and more sustained drop in blood pressure compared to apelin-13. Our study identified new potent analogues of apelin-13, which represent valuable probes to better understand its structure–function relationship