This SBIR Phase I feasibility study aims to implement a novel strategy for the development aggregation inhibitors as treatments for Alzheimer's Disease (AD), Parkinson's Disease (PD), and potentially other amyloid and protein misfolding diseases. Amyloid diseases are characterized by transformation of proteins from their proper native structure into an abnormal beta-rich structure known as amyloid fibril. This process is triggered by short peptide segments within the polypeptide sequence called core nucleation motifs that readily convert from alpha-helix or random coil in their native state to beta-strand. We refer to this trait as hidden beta-strand propensity (HbP). A viable therapeutic strategy for fibril elimination is to design aggregation inhibitors that specifically target these core nucleation motifs. We will therefore implement our novel computational tool called the HbP method to target these core nucleation motifs. The HbP method possesses the remarkable capability to identify non-native beta-prone regions in polypeptides or full-length proteins. The core nucleation motifs identified by our HbP tool will then serve as targets for our aggregation inhibitor designs. In this study, we will target three proteins relevant to neurological disorders: Abeta (AD), alpha-synuclein (AD, PD), and Tau (AD). Our design scheme for these aggregation inhibitors is based on the concept of multifunctional PEG-peptide conjugates containing multiple binding elements interacting with multiple sites on the aggregated protein (i.e., amyloid plaques). The use of Polyethylene Glycol (PEG) will improve in vivo half-life, water solubility, transport properties (intestinal and blood-brain barrier transport), and resistance to enzymatic degradation, while the use of multiple inhibitors will improve avidity and selectivity for the amyloid plaques. Our integrated research plan combines target identification; computer-aided inhibitor design; chemical synthesis; and biological evaluation of aggregation inhibitors. Our overall goal is the discovery of candidate aggregation inhibitors for future preclinical testing in animal models leading eventually to clinical testing of potential therapeutic agents.This SBIR Phase I feasibility study aims to implement a novel strategy for the development aggregation inhibitors as treatments for Alzheimer's Disease (AD), Parkinson's Disease (PD), and potentially other amyloid and protein misfolding diseases.
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