2 research outputs found
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