Synthetic Study on Neurotrophins and Its Application for Development of Diagnostic Immunoassay Method for Senile Dementia

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The following investigations were caried out for development of diagnostic immunoassay method for senile dementia. The report which deny the significant correlation between the plasma levels of neurotrophins and Alzheimer's disease forced us to change the initial plan, however, basic study conducted here should contribute to the future research on daignostic and/or therapeutic use of neurotrophins for senile dementia.1. A new chemoselective purication method of synthetic peptides based on the bifunctional SH-introducing reagent was developed. In addition, specific affinity purification method using a reversible biotinylating reagent was developed for the final purification of synthetic peptides by solid phase technique.2. Synthetic study on neuroprophins was carried out in combination with newly-developed chemoseletcive purification method of synthetic peptides and fragment condensation method on solid support. However, low purification yields of Cys-containing peptide fragments and lo … More wering yields in solid phase fragment condensations along with chain elongation compelled us to abandon the total synthesis of neurotrophins.3. In order to facilitate the final disulfide bond formation of neurotrophins containing three disulfide bonds, new sulfoxide-mediated disulfide bond- forming reactions were developed and successfully applied for unambiguous regioselectie sidulfide-bond formation of several biologically active peptides including anti-HIV peptides and memory enhancing peptides which stimulate NGF synthesis.4. In order to investigate the intracellular signal transductin pathway of neurotrophin Trk-receptors and the abnormal phosphorylations of Tau-protein associated with Alzheimer's Disease, an efficient synthetic method of phosphopeptides by solid phase technique was developed. Furthermore, stereoselective synthetic methods of phosphatase-resisted phosphoaminoacids mimetics and (E) -alkene-dipeptide isoseres as nonhydrolyzable dipeptide mimetics were investigated. These nonhydrolyzable phosphopeptide mimetics will serve as useful tools for biochemical study on protein phosphorylation associated with Alzheimer's disease. Less