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.