Numerous genetic factors are associated with obesity. Agouti-related protein (AGRP), an endogenous antagonist for the melanocortin 3 and 4 receptors (MC3R and MC4R), is one such factor. Overexpression or exogenous delivery of AGRP results in an increase in food intake, perturbing energy homeostasis. Studying AGRP may therefore lead to probes that could offer new insights into the etiology and potential treatment for obesity, and also may lead to novel therapeutics for negative energy disease states such as cachexia associated with cancer. The C-terminal domain of AGRP has previously been shown to be equipotent for binding and activity compared to the full length 132 residue protein. Despite the purported pharmacophore of AGRP consisting of an Arg-Phe-Phe three residue sequence, previous efforts to truncate the C-terminal domain typically result in decreased potency. A recent report of a novel peptide scaffold, c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro], based upon stabilization of the ?-hairpin loop of AGRP containing the pharmacophore, described potent octapeptides that were equipotent to AGRP. The purpose of the present application is to understand the molecular basis of the c[Pro-Arg-Phe-Phe- Asn-Ala-Phe-DPro] octapeptide scaffold with the MC4R. Select octapeptides will be studied by 2D 1H NMR and computer assisted molecular modeling to examine the solution structures of these MC4R ligands, in attempts to correlate structure with function. Potent octapeptide ligands will be subjected to peptoid residue scans, as a first step towards translating the observed bench side activity into bedside therapeutics and potentially make more potent and stable ligands. A proposed AGRP-MC4R ligand-receptor interaction will also be probed, potentially identifying a site in the MC4R that can be exploited to generate more potent ligands. Overall, this project is expected to examine a new class of MC4R specific ligands that are based upon AGRP; such ligands may bypass the side-effects of the MC4R ligands previously used in clinical trials that were derived from synthetic modification of endogenous agonists.
The majority of the population in the US is considered overweight and obese. Agouti-related protein (AGRP) is one genetic risk factor for developing obesity. By developing small molecules based upon AGRP, we hope to develop novel probes and therapeutics to better understand and treat obesity and other eating disorders.
