The long term goals of this research are to develop a multi disciplinary research 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) with emphasis on the melanocortin receptors. 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;macrocyclicpeptide and peptidomimetic synthetic methods;the utilization of cloned GPCRs for binding and second messenger assays, and for examination of mechanisms of signal transduction;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 propiomelanocortin peptides (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 synthesis methods for novel amino acid and molecular templates which will be used in the design and synthesis of novel ligands which are potent and selective agonists or antagonists or inverse agonists for the hMC1R, hMC3R, hMC4R and hMC5R;2) their evaluation in binding affinity and second messenger assays, and examination by computational and biophysical methods of the conformational features that are critical for these potencies and receptor selectivities;and 3) use of a variety of biochemical, biophysical, and molecular pharmacology methods to examine the biological properties which lead to different signaling and/or which can explain the selectivity of these ligand and discover unique properties which can be used for further design of new ligands the enhanced properties in Specific Aim 1.
The melanotropin peptides are hormones and neurotransmitters that interact with their cognate receptors on the cell surface (melanocortin receptors) and affect many critical aspects of human health, disease and behavior. Important affects include feeding behavior, obesity, anorexia, pain, diabetes, pigmentary disorders, cancer, sexual response and motivation, immune response, and many others. We are developing highly selective agonists and antagonists for these systems and using these ligands to study the mechanisms of action that lead to these responses and to develop these ligands as potential drugs to treat diseases and behavior abnormalities.
|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|
|Mayorov, Alexander V; Cai, Minying; Palmer, Erin S et al. (2011) Cyclic lactam hybrid ýý-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors. Bioorg Med Chem Lett 21:3099-102|
Showing the most recent 10 out of 145 publications