Dissertation/Thesis Abstract

Identification and design of small molecules that associate with aggregated Alzheimer's-related beta-amyloid peptides
by Bautista, Mahealani Roberts, Ph.D., University of California, San Diego, 2009, 220; 3344755
Abstract (Summary)

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.

Indexing (document details)
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, Pharmacy sciences
Keywords: Alpha synuclein, Alzheimer's disease, Beta-amyloid peptides, Small molecules, Therapeutic and diagnostic agents
Publication Number: 3344755
ISBN: 9781109039504
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