Peptidomimetic Long-Acting Growth Hormone-Releasing Hormone Agonists Promote Tissue Perfusion in Hindlimb Ischemia

Growth
hormone-releasing hormone (GHRH) has shown therapeutic potential
in the treatment of various diseases. However, the clinical translation
of GHRH receptor (GHRH-R) agonists has been hampered by the short
half-life and suboptimal activity. Herein, we report a series of hybrid
GHRH analogs developed using sulfono-γ-AA peptide-based peptidomimetic
optimization. These hybrid peptides exhibit significantly enhanced
potency in activating GHRH-R and stimulating growth hormone release
while demonstrating markedly improved serum stability (T1/2 > 24 h). Subcutaneous administration of selected
peptides
in mice with ischemic hindlimb enhanced blood perfusion and preservation
of limb function. They also promoted endothelial regeneration and
collateral vessel formation, enhancing vascular remodeling and tissue
repair. In vitro, the peptides enhanced the angiogenic potential of
endothelial cells, primarily through activation of the ERK signaling
pathway. Our findings lay a strong foundation for the development
of long-acting GHRH-R agonists with promising therapeutic potential
for the treatment of vascular and regenerative disease.