Identification and design of small molecules that associate with aggregated Alzheimer's-related beta-amyloid peptides
Aggregated beta-amyloid peptides have been identified as a pathological hallmark of Alzheimer's Disease (AD). Presented in this dissertation is the identification, evaluation, and design of small molecules that bind to aggregated beta-amyloid peptides. First, this dissertation describes the development of a parallel assay to rapidly screen small- to medium-sized libraries of molecules for their ability to bind to aggregated beta-amyloid(1-42) peptides. It also describes the extension of this assay to identify molecules that associate with two other amyloidogenic peptides, beta-amyloid(1-40) and alpha- synuclein(1-140), which revealed some selectivity for the association of specific small molecules to different amyloids. Second, it describes the development of amyloid- binding molecules that are capable of inhibiting protein- amyloid interactions, which may lead to a new therapeutic strategy for combating amyloid-based neurodegenerative disorders. Specifically, it describes the synthesis and evaluation of derivatives of thioflavin T, nicotine, and dopamine for their ability to inhibit protein-amyloid interactions. An extensive evaluation of derivatives of dopamine revealed the minimum structural requirements necessary to effectively inhibit the interaction between aggregated beta-amyloid peptides. Lastly, it describes studies towards the rational design of a novel class of imaging agents for AD based on information from the structure-binding studies with derivatives of dopamine.