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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.
Advisor: | Yang, Jerry |
Commitee: | Fenical, William, Figueroa, Joshua, Perrin, Charles L., Sosinsky, Gina, Tor, Yitzhak |
School: | University of California, San Diego |
Department: | Chemistry |
School Location: | United States -- California |
Source: | DAI-B 70/02, Dissertation Abstracts International |
Source Type: | DISSERTATION |
Subjects: | Analytical chemistry, Organic chemistry |
Keywords: | Alpha synuclein, Alzheimer's disease, Beta-amyloid peptides, Small molecules, Therapeutic and diagnostic agents |
Publication Number: | 3344755 |
ISBN: | 978-1-109-03950-4 |