? The long term goals of this research are to develop a multidisciplinary research program that provides a systematic, rational, three dimensional approach to the design and synthesis of potent receptor/acceptor selective peptide and peptide mimetic ligands for peptide hormones and neurotransmitter G-protein coupled receptors (GPCRs). This research requires a highly multidisciplinary approach including: computer assisted modeling; conformational analysis using 2D NMR spectroscopy and other biophysical methods; novel asymmetric synthetic methods; macrocyclic peptide and peptidomimetic synthetic methods; the utilization of cloned GPCRs for binding and second messenger assays; and for evaluation of conformation-biological activity relationships that lead to receptor selective and potent peptides and peptidomimetics with specific agonist and antagonist biological activities; to develop a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy that allows for the first time direct observation of the structural changes that accompany ligand-GPCR interactions in membranes. Specifically, this grant will focus on ligands which are derived from proopiomelanocortin (e.g. alpha-MSH, gamma-MSH, etc.), and that interact with human melanocortin receptors MC1R, MC3R, MC4R and MC5R.
Specific aims i nclude: 1) development of novel asymmetric synthetic methods for conformationally and topographically constrained novel amino acids, chimeric amino acids, beta-turn mimetics, and other templates for design of novel peptide and peptide mimetic melanotropins; 2) to develop novel, potent and selective structures which are ligands for the hMC1R, hMC3R, hMC4R and hMC4R; 3) to use stable transfected cell lines to evaluate ligand-receptor binding affinities, second messenger activities, and other bioactivities; 4) to use computer assisted modeling, computational chemistry, conformational analysis and related methods to develop and test models of agonist and antagonist bioactivity; 5) to develop PWR spectroscopy into a powerful tool for examining in real time the structural differences of ligand receptor complexes that are respectively agonist, antagonist, or inverse agonist induced; 6) finally we will work closely with biologists and others worldwide to develop novel insights into the bioactivities of melanotropins and melanocortin receptors (pigmentation, feeding behavior, sexual behavior, immune response, pain, etc.). ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK017420-31
Application #
6984782
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (03))
Program Officer
Sechi, Salvatore
Project Start
1977-09-30
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
31
Fiscal Year
2006
Total Cost
$288,378
Indirect Cost
Name
University of Arizona
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Mowlazadeh Haghighi, Saghar; Zhou, Yang; Dai, Jixun et al. (2018) Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation. Eur J Med Chem 151:815-823
Zhou, Yang; Mowlazadeh Haghighi, Saghar; Zoi, Ioanna et al. (2017) Design of MC1R Selective ?-MSH Analogues with Canonical Amino Acids Leads to Potency and Pigmentation. J Med Chem 60:9320-9329
Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake et al. (2017) Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. Biochemistry 56:4201-4209
Hruby, Victor J (2016) Design of cyclic peptides with biological activities from biologically active peptides: the case of peptide modulators of melanocortin receptors. Biopolymers 106:884-888
Cai, Minying; Marelli, Udaya Kiran; Bao, Jennifer et al. (2015) Systematic Backbone Conformational Constraints on a Cyclic Melanotropin Ligand Leads to Highly Selective Ligands for Multiple Melanocortin Receptors. J Med Chem 58:6359-67
Carotenuto, Alfonso; Merlino, Francesco; Cai, Minying et al. (2015) Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor. J Med Chem 58:9773-8
Brabez, Nabila; Saunders, Kara; Nguyen, Kevin L et al. (2013) Multivalent Interactions: Synthesis and Evaluation of Melanotropin Multimers - Tools for Melanoma Targeting. ACS Med Chem Lett 4:98-102
Cai, Minying; Stankova, Magda; Muthu, Dhanasekaran et al. (2013) An unusual conformation of ?-melanocyte-stimulating hormone analogues leads to a selective human melanocortin 1 receptor antagonist for targeting melanoma cells. Biochemistry 52:752-64
Liu, Zhihua; Mehta, Sukeshi J; Lee, Kwang-Soo et al. (2012) Thio-Claisen rearrangement used in preparing anti-ýý-functionalized ýý,ýý-unsaturated amino acids: scope and limitations. J Org Chem 77:1289-300
Yamamoto, Takashi; Nair, Padma; Largent-Milnes, Tally M et al. (2011) Discovery of a potent and efficacious peptide derivative for ýý/ýý opioid agonist/neurokinin 1 antagonist activity with a 2',6'-dimethyl-L-tyrosine: in vitro, in vivo, and NMR-based structural studies. J Med Chem 54:2029-38

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