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.