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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

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    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
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    † †Department of Pharmacodynamics and ‡Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, United States
    *Before June 2011: (phone) (352) 273-7717; (e-mail) [email protected]. After July 2011: (address) Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford Hall, 308 Harvard Street, SE, Minneapolis, MN, 55455; (e-mail) email:[email protected]; phone and fax unknown as of January 2011.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2011, 54, 5, 1379–1390
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm101425m
    Published February 9, 2011
    Copyright © 2011 American Chemical Society
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    Abstract

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    By use of a solid-phase synthetic approach, a bioactive reverse turn heterocycle was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R−MC5R) are G-protein-coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nanomolar potency. Biophysical structural analysis [2D 1H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families compared to the reference peptide and result in a novel template for further structure−function studies.

    Copyright © 2011 American Chemical Society

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    Cited By

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    This article is cited by 13 publications.

    1. Luis E. Gimenez, Charlotte Martin, Jing Yu, Charlie Hollanders, Ciria C. Hernandez, Yiran Wu, Deqiang Yao, Gye Won Han, Naima S. Dahir, Lijie Wu, Olivier Van der Poorten, Arthur Lamouroux, Morgane Mannes, Suwen Zhao, Dirk Tourwé, Raymond C. Stevens, Roger D. Cone, Steven Ballet. Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design. Journal of Medicinal Chemistry 2024, 67 (4) , 2690-2711. https://doi.org/10.1021/acs.jmedchem.3c01822
    2. Angelina Osipyan, Alexander Sapegin, Alexander S. Novikov, Mikhail Krasavin. Rare Medium-Sized Rings Prepared via Hydrolytic Imidazoline Ring Expansion (HIRE). The Journal of Organic Chemistry 2018, 83 (17) , 9707-9717. https://doi.org/10.1021/acs.joc.8b01210
    3. Srinivasa R. Tala, Anamika Singh, Cody J. Lensing, Sathya M. Schnell, Katie T. Freeman, James R. Rocca, Carrie Haskell-Luevano. 1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization. ACS Chemical Neuroscience 2018, 9 (5) , 1001-1013. https://doi.org/10.1021/acschemneuro.7b00422
    4. Mark D. Ericson, Katie T. Freeman, Sathya M. Schnell, and Carrie Haskell-Luevano . A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands. Journal of Medicinal Chemistry 2017, 60 (2) , 805-813. https://doi.org/10.1021/acs.jmedchem.6b01707
    5. Anamika Singh, Srinivasa R. Tala, Viktor Flores, Katie Freeman, and Carrie Haskell-Luevano . Synthesis and Pharmacology of α/β3-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence. ACS Medicinal Chemistry Letters 2015, 6 (5) , 568-572. https://doi.org/10.1021/acsmedchemlett.5b00053
    6. Anamika Singh, Marvin L. Dirain, Andrzej Wilczynski, Chi Chen, Blake A. Gosnell, Allen S. Levine, Arthur S. Edison, and Carrie Haskell-Luevano . 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 Chemical Neuroscience 2014, 5 (10) , 1020-1031. https://doi.org/10.1021/cn5000953
    7. Erica M. Haslach, Huisuo Huang, Marvin Dirain, Ginamarie Debevec, Phaedra Geer, Radleigh G. Santos, Marc A. Giulianotti, Clemencia Pinilla, Jon R. Appel, Skye R. Doering, Michael A. Walters, Richard A. Houghten, and Carrie Haskell-Luevano . 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). Journal of Medicinal Chemistry 2014, 57 (11) , 4615-4628. https://doi.org/10.1021/jm500064t
    8. Anamika Singh, Marvin Dirain, Rachel Witek, James R. Rocca, Arthur S. Edison, and Carrie Haskell-Luevano . 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 Melanocortin-4 Receptor (mMC4R). Journal of Medicinal Chemistry 2013, 56 (7) , 2747-2763. https://doi.org/10.1021/jm301253y
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    11. Hsin-Chieh Tang, Calvin Yu-Chian Chen, . Investigation of the Novel Lead of Melanocortin 1 Receptor for Pigmentary Disorders. Evidence-Based Complementary and Alternative Medicine 2014, 2014 (1) https://doi.org/10.1155/2014/254678
    12. Kuruppanthara N. Vijayadas, Roshna V. Nair, Rupesh L. Gawade, Amol S. Kotmale, Panchami Prabhakaran, Rajesh G. Gonnade, Vedavadi G. Puranik, Pattuparambil R. Rajamohanan, Gangadhar J. Sanjayan. Ester vs. amide on folding: a case study with a 2-residue synthetic peptide. Organic & Biomolecular Chemistry 2013, 11 (48) , 8348. https://doi.org/10.1039/c3ob41967c
    13. Workalemahu M Berhanu, Mohamed A Ibrahim, Girinath G Pillai, Alexander A Oliferenko, Levan Khelashvili, Farukh Jabeen, Bushra Mirza, Farzana Latif Ansari, Ihsan ul-Haq, Said A El-Feky, Alan R Katritzky. Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics. Beilstein Journal of Organic Chemistry 2012, 8 , 1146-1160. https://doi.org/10.3762/bjoc.8.128
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2011, 54, 5, 1379–1390
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm101425m
    Published February 9, 2011
    Copyright © 2011 American Chemical Society
    Request reuse permissions

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