3 research outputs found
CāTerminal Modifications of Apelin-13 Significantly Change Ligand Binding, Receptor Signaling, and Hypotensive Action
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 Phe<sup>13</sup> residue
on ligand binding, receptor signaling, and hypotension, we report
a series of modified analogues in which Phe<sup>13</sup> 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 Bpa<sup>13</sup> or
(Ī±-Me)ĀPhe<sup>13</sup> were 30-fold more potent to inhibit cAMP
accumulation than apelin-13. TyrĀ(OBn)<sup>13</sup> 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 structureāfunction
relationship
A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects
The apelin receptor
generates increasing interest as a potential
target across several cardiovascular indications. However, the short
half-life of its cognate ligands, the apelin peptides, is a limiting
factor for pharmacological use. In this study, we systematically explored
each position of apelin-13 to find the best position to cyclize the
peptide, with the goal to improve its stability while optimizing its
binding affinity and signaling profile. Macrocyclic analogues showed
a remarkably higher stability in rat plasma (half-life >3 h versus
24 min for Pyr-apelin-13), accompanied by improved affinity (analogue <b>15</b>, <i>K</i><sub>i</sub> 0.15 nM and <i>t</i><sub>1/2</sub> 6.8 h). Several compounds displayed higher inotropic
effects ex vivo in the Langendorff isolated heart model in rats (analogues <b>13</b> and <b>15</b>, maximum response at 0.003 nM versus
0.03 nM of apelin-13). In conclusion, this study provides stable and
active compounds to better characterize the pharmacology of the apelinergic
system
A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects
The apelin receptor
generates increasing interest as a potential
target across several cardiovascular indications. However, the short
half-life of its cognate ligands, the apelin peptides, is a limiting
factor for pharmacological use. In this study, we systematically explored
each position of apelin-13 to find the best position to cyclize the
peptide, with the goal to improve its stability while optimizing its
binding affinity and signaling profile. Macrocyclic analogues showed
a remarkably higher stability in rat plasma (half-life >3 h versus
24 min for Pyr-apelin-13), accompanied by improved affinity (analogue <b>15</b>, <i>K</i><sub>i</sub> 0.15 nM and <i>t</i><sub>1/2</sub> 6.8 h). Several compounds displayed higher inotropic
effects ex vivo in the Langendorff isolated heart model in rats (analogues <b>13</b> and <b>15</b>, maximum response at 0.003 nM versus
0.03 nM of apelin-13). In conclusion, this study provides stable and
active compounds to better characterize the pharmacology of the apelinergic
system