Obesity afflicts millions of people, and is a major risk factor for Type II diabetes and morbidity. The melanocortin pathway has been clearly identified in mice and humans to be involved in the regulation of satiety, obesity, and energy homeostasis. The goal of this research project is characterize the human melanocortin-4 receptor (MC4R) N- terminal 1-26 domain peptide agonist, identify how it molecularly interacts with the MC4R to mechanistically function as a full agonist. These data will be used to generate novel and potent MC4R agonist molecules as molecular probes and potential central nervous system (CNS) drugs. The impact of the anticipated results on the medicinal chemistry and obesity research fields could challenge the existing paradigms for ligand design strategies for melanocortin receptor based therapeutics, GPCR based therapeutics, as well as provide novel tools to probe weight and energy homeostasis.

Public Health Relevance

Obesity is a complex disease and is a risk factor for several other associated diseases. The melanocortin pathway has been identified in mice and humans, to regulate obesity. The goal of this research project is characterize the human melanocortin-4 receptor (MC4R) N-terminal 1-26 domain peptide agonist, identify how it molecularly interacts with the MC4R to mechanistically function as a full agonist. The impact of the anticipated results on the medicinal chemistry and obesity research fields could challenge the existing paradigms for ligand design strategies for melanocortin receptor based therapeutics, GPCR based therapeutics, as well as provide novel tools to probe weight and energy homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK108893-03
Application #
9449442
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pawlyk, Aaron C
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Ericson, Mark D; Singh, Anamika; Tala, Srinivasa R et al. (2018) Human ?-Defensin 1 and ?-Defensin 3 (Mouse Ortholog mBD14) Function as Full Endogenous Agonists at Select Melanocortin Receptors. J Med Chem 61:3738-3744
Adank, Danielle N; Lunzer, Mary M; Lensing, Cody J et al. (2018) Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice. ACS Chem Neurosci 9:320-327
Lensing, Cody J; Adank, Danielle N; Wilber, Stacey L et al. (2017) A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage. ACS Chem Neurosci 8:1262-1278
Ericson, Mark D; Lensing, Cody J; Fleming, Katlyn A et al. (2017) Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016. Biochim Biophys Acta Mol Basis Dis 1863:2414-2435