Misfolded, amyIold-Iike protein deposits in cells and tissues are commonly associated with numerous human diseases, including Alzheimer's disease (AD), prion diseases (e.g. Creutzfeldt-Jakob disease), Parkinson's disease, Type-ll diabetes etc. representing tremendous medical, social and financial problems. The Alzheimer's disease involves the formation of extracellular amyloid-beta (Abeta) peptide into fibrillar deposits known as amyloid plaques (senile plaques). These fibrils (polymeric aggregates) or soluble oligomeric intermediates of Abeta peptide (or both) are associated with pathology. Accordingly, the inhibition of both seeding and fibril growing process in Abeta self-assembly is a promising therapeutic strategy. The goal of this proposal is to design and synthesize a new class of antifibrillogenic compounds. Based on literature data and encouraging preliminary results, we predict that a wide variety of our new compounds, such as CF3- containing indole-3-yl carboxylic acid derivatives and their higher analogs (peptidomimetics), will be able to inhibit the formation of amyloid oligomers and fibrils, and also might be able to reverse the oligomerization process. The inhibitors will be synthesized by our recently developed chiral organocatalytic process. The effect of inhibitors on fibrillogenesis will be tested in vitro by thioflavin-T fluorescence spectroscopy, Congo Red binding and high resolution transmission electron microscopy. A quantitative structure-activity relationship (QSAR) of the inhibitors will be determined. One series of experiments is designed to determine the inhibition, of Abeta fibrillogenesis, while another will describe whether these compounds are able to reverse the aggregation process, i.e. clear the already formed oligomers/fibrils. In the proposal, we will test our hypothesis with the fundamental goal of defining a new class of effective antifibrillogenic compounds, which, in turn, could lead to gain new insights into the mechanism of protein misfolding and amyloidogenesis and ultimately to the discovery of novel drug candidates against AD and related amyloid disorders.
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