Agouti-related protein (AGRP) and agouti (ASP) are the only two naturally occurring antagonists of G protein coupled receptors (GPCRs) identified to date, and when over expressed in mice, result in an obese phenotype. Obesity (body mass index >25) afflicts millions of people in the United States (an estimated 97 million adults in the U.S.) and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke and hypertension. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 25 pathways that have been identified to participate in and regulate feeding behavior and energy homeostasis. The melanocortin pathway includes five such genetic factors that have been demonstrated to mediate weight homeostasis, and when modified, result in obesity. The melanocortin pathway includes the melanocortin agonists, derived from the preprohormone proopiomelanocortin (POMC) gene transcript, the five melanocortin receptors identified to date (MC1R-MC5R), and the only 2 naturally occurring antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP). The five melanocortin genetic factors identified as being involved in energy homeostasis are POMC, ASP, AGRP, and the brain specific melanocortin-4 (MC4R) and the melanocortin-3 (MC3R) receptors. AGRP and ASP are paracrine factors that antagonize the melanocortin receptors. Specifically, ASP antagonizes the skin melanocortin-1 receptor (MC1R) and the brain MC4R. AGRP normally only antagonizes the melanocortin receptors in the brain, MC3R and MC4R. A polymorphism has been identified in humans diagnosed with anorexia nervosa, linking AGRP with a human physiological disease state. Both ASP and AGRP are 131-132 amino acids in length (depending upon species), and possess a C-terminal domain that putatively contains 5 disulfide bridges. The C-terminal domain has been identified as the region of the protein that possesses antagonistic properties at the melanocortin receptors. These data support the hypothesis that AGRP and ASP are involved in the regulation of melanocortin receptor mediated physiological pathways. The research objectives of this proposal are to 1) identify structural determinants of the AGRP protein important for molecular recognition and functional activity at melanocortin receptor proteins, and 2) identify putative AGRP-MC4 receptor interactions. In addition to generating structural and functional information about one of the only two endogenous GPCR antagonists, new tools will be developed which may be utilized in vivo to gain a broader understanding of the physiological mechanism(s) resulting in obesity and skin pigmentation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064250-04
Application #
7014484
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Sato, Sheryl M
Project Start
2003-04-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$208,682
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Ericson, Mark D; Wilczynski, Andrzej; Sorensen, Nicholas B et al. (2015) Discovery of a ?-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology. J Med Chem 58:4638-47
Haslach, Erica M; Huang, Huisuo; Dirain, Marvin et al. (2014) Identification of tetrapeptides from a mixture based positional scanning library that can restore nM full agonist function of the L106P, I69T, I102S, A219V, C271Y, and C271R human melanocortin-4 polymorphic receptors (hMC4Rs). J Med Chem 57:4615-28
Singh, Anamika; Dirain, Marvin L; Wilczynski, Andrzej et al. (2014) Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R). ACS Chem Neurosci 5:1020-31
Singh, Anamika; Dirain, Marvin; Witek, Rachel et al. (2013) Structure-activity relationships of peptides incorporating a bioactive reverse-turn heterocycle at the melanocortin receptors: identification of a 5800-fold mouse melanocortin-3 receptor (mMC3R) selective antagonist/partial agonist versus the mouse melano J Med Chem 56:2747-63
Irani, Boman G; Xiang, Zhimin; Yarandi, Hossein N et al. (2011) Implication of the melanocortin-3 receptor in the regulation of food intake. Eur J Pharmacol 660:80-7
Singh, Anamika; Wilczynski, Andrzej; Holder, Jerry R et al. (2011) Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR. J Med Chem 54:1379-90
Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L et al. (2010) Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist. Biochemistry 49:4583-600
Singh, Anamika; Haslach, Erica M; Haskell-Luevano, Carrie (2010) Structure-activity relationships (SAR) of melanocortin and agouti-related (AGRP) peptides. Adv Exp Med Biol 681:1-18
Schaub, Jay W; Bruce, Erin B; Haskell-Luevano, Carrie (2010) Drugs, exercise, and the melanocortin-4 receptor-- different means, same ends: treating obesity. Adv Exp Med Biol 681:49-60

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