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.
Showing the most recent 10 out of 145 publications
