The long term goals of this research are to develop a more rational approach to the design of potent, receptor selective peptide hormone and neurotransmitter ligands, and to obtain an understanding of the physical-chemical basis for information transfer by peptide hormones and neurotransmitters. More specifically we seek to design peptide molecules with conformational properties that differentiate those aspects of hormone- receptor interactions that are related to biological activity, in particular recognition, transduction, and reversal. A major approach being developed to aid in these goals is that of conformational and topographical constraint. Development of this approach will lead to peptide analogues with high potency, high receptor specificity, antagonist activities, prolonged in vitro and in vivo activity, and other desired biological properties.
Specific aims i nclude the following: 1) continued development of asymmetric synthesis methods, of new methods for preparing cyclic analogues on solid supports, and of other synthetic and analytical methods required by our design work; 2) development of the concepts of conformational and topographical constraint to obtain highly potent and receptor selective melanotropin agonists and antagonists; 3) use of the concepts of conformational and topographical constraint to probe the conformational and structural requirements for oxytocin agonists and antagonists; 4) determine the conformational and structural properties of melanocyte concentrating hormone related to its biological activities; 5) utilize biophysical methods such as 1D and 2D NMR, circular dichroism, molecular mechanics calculations and molecular dynamics simulations in conjunction with computer assisted modeling to determine conformations of peptide analogues and to derive models for peptide conformation-biological activity relationships; and 6) use of biophysical methods, especially NMR, to determine the conformations of peptides when bound to acceptor proteins, using the neurohypophyseal hormone-neurophysin system as a model. This research will be highly interdisciplinary including nearly all aspects of chemistry (synthetic, analytical, physical and biochemical), close collaborations with biologists, and critical use of biophysical methods to obtain new insights into peptide structure-conformation relationships and their relation to biological activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK017420-20
Application #
3225743
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1977-09-30
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
20
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Arts and Sciences
DUNS #
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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