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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK108402-03
Application #
9387438
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2015-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
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
Fleming, Katlyn A; Ericson, Mark D; Freeman, Katie T et al. (2018) Structure-Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake in Mic ACS Chem Neurosci 9:1141-1151
Ericson, Mark D; Koerperich, Zoe M; Freeman, Katie T et al. (2018) Arg-Phe-Phe d-Amino Acid Stereochemistry Scan in the Macrocyclic Agouti-Related Protein Antagonist Scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro] Results in Unanticipated Melanocortin-1 Receptor Agonist Profiles. ACS Chem Neurosci :
Fleming, Katlyn A; Freeman, Katie T; Ericson, Mark D et al. (2018) Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists. J Med Chem 61:7729-7740
Ericson, Mark D; Haskell-Luevano, Carrie (2018) A Review of Single-Nucleotide Polymorphisms in Orexigenic Neuropeptides Targeting G Protein-Coupled Receptors. ACS Chem Neurosci 9:1235-1246
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
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
Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M et al. (2017) A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]?-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands. J Med Chem 60:805-813
Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M et al. (2017) Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at t J Med Chem 60:8103-8114
Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D et al. (2016) Comparative Functional Alanine Positional Scanning of the ?-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors. ACS Chem Neurosci 7:984-94