Sustained Activation of CLR/RAMP Receptors by Gel-Forming Agonists.

Background

Adrenomedullin (ADM), adrenomedullin 2 (ADM2), and CGRP family peptides are important regulators of vascular vasotone and integrity, neurotransmission, and fetoplacental development. These peptides signal through CLR/RAMP1, 2, and 3 receptors, and protect against endothelial dysfunction in disease models. As such, CLR/RAMP receptor agonists are considered important therapeutic candidates for various diseases. Methods and

Results

Based on the screening of a series of palmitoylated chimeric ADM/ADM2 analogs, we demonstrated a combination of lipidation and accommodating motifs at the hinge region of select peptides is important for gaining an enhanced receptor-activation activity and improved stimulatory effects on the proliferation and survival of human lymphatic endothelial cells when compared to wild-type peptides. In addition, by serendipity, we found that select palmitoylated analogs self-assemble to form liquid gels, and subcutaneous administration of an analog gel led to the sustained presence of the peptide in the circulation for >2 days. Consistently, subcutaneous injection of the analog gel significantly reduced the blood pressure in SHR rats and increased vasodilation in the hindlimbs of adult rats for days.

Conclusions

Together, these data suggest gel-forming adrenomedullin analogs may represent promising candidates for the treatment of various life-threatening endothelial dysfunction-associated diseases such as treatment-resistant hypertension and preeclampsia, which are in urgent need of an effective drug.