The long range goal of this research is to obtain an understanding of the physical-chemical basis for information transfer by peptide hormones and neurotransmitters. In particular, we seek an understanding of those aspects of peptide conformational structure which are required for and those which differentiate the various aspects of direct hormone-receptor interactions thought to be related to biological activity, especially recognition (binding, potency), transduction (efficacy, inhibition), and reversal (duration of action). The utilization of this understanding to develop peptide hormone and neurotransmitter analogues with super potency, high receptor specificity, antagonist activities, prolonged in vitro and in vivo activity, etc. is always a primary goal.
Specific aims i nclude: 1) development of the synthetic, purification, and analytical methods necessary to prepare whatever amino acid derivatives and peptide hormone analogues are needed; 2) development of the use of conformational and topological considerations to probe the physical-chemical basis for peptide hormone biological activity; 3) further development of strategies for obtaining highly receptor specific, potent, prolonged acting agonist and antagonist analogues, especially of the neurohypophyseal hormones and the melanotropins; 4) use of NMR, CD, and other biophysical methods to obtain insights into conformational structure-biological activity relationships; 5) examination of the nature of a hormone-receptor (acceptor) interaction using the neurohypophyseal hormone-neurophysin system; and 6) examination of conformational structure-biological activity relationships for the recently discovered melanocyte concentrating hormone. This research requires a multidisciplinary approach which includes modern synthetic organic chemistry, bio-analytical chemistry, biophysical techniques, and careful application and analysis of biological assay results and techniques. Utilization and development of new methods and approaches for the synthesis of desired amino acids and peptides, for HPLC and partition chromatography separation and purification of peptides, and for appropriate application of NMR, CD, and other biophysical methods are essential for the attainment of our overall goals. Close collaboration with several biologists provides critical biological data essential for this research.
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