PEPTIDE HORMONE STRUCTURE AND FUNCTION

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 include: 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.