The long term goal of this research program is to expand the basic knowledge of biological information transfer from nerve cell to target cell by peptides. This particular research focuses on the final stages of neuroendocrine processes where the information is transferred from the peptide messenger to the target cell receptor. We will concentrate on both the molecular properties of the hormone and the structure of the receptor. The model for our research is the insect hypertrehalosemic neurohormone (HTH, pGlu-Val-Asn-Phe-Ser-Pro-Gly-Trp-Gly-Thr-NH2). The hormone was isolated from nerve tissue of the tropical cockroach Blaberus discoidalis by our laboratory. The major observed function of this peptide in B. discoidalis is elevation of blood sugar concentration, an action similar to that of glucagon in vertebrates. The unique and extensive knowledge of this laboratory for HTH structure-activity relationships will be the basis for the research approach. The research at Texas A & M will continue to use this non- controversial laboratory organism (B. discoidalis) to expand knowledge about neuroendocrine systems and peptide-receptor interactions. This laboratory is working closely with organic chemists whose major goal is the development of peptide beta-turn mimetics for potential pharmaceuticals for the treatment of AIDS and Alzheimer's disease. HTH is a good model to test the beta-turn mimetics developed by our collaborators because our structure- activity studies suggest that a beta-turn in HTH orients other critical residues for receptor interaction. Simple, economical assays are available to test the results of mimetic inclusion . The information that we glean from this model system can provide assistance for the design of future pharmaceuticals and the development of rational plans for insect control leading to a reduction of vector-borne diseases. The specific objectives of the proposed research are to use peptide synthesis and peptide analysis in conjunction with our assay systems to: 1. Develop radioHTH-receptor binding assays to characterize receptor tissue distribution, occupancy and kinetic parameters; 2. Develop radioHTH photoaffinity probes to confirm receptor tissue distribution and gain molecular information on receptor molecules; 3. Continue analog studies to determine the properties of HTH required for binding and signal transduction, and attempt to develop receptor antagonists through the use of restricted conformational analogs and mimetics.
