Synthesis and Biological Evaluation of (Hydroxethyl) Urea Peptidomimetic Transition-State Analogs for Use in a Click Chemistry Approach to Studying the Gamma-Secretase Complex

Eric Gars

Date of Award

2009

Document Type

Thesis

Degree Name

Bachelors

Department

Natural Sciences

First Advisor

Scudder, Paul

Keywords

Synthesis, Alzheimer's Disease, Click Chemistry

Area of Concentration

Biochemistry

Abstract

Alzheimer's disease (AD) is an incurable, neurodegenerative, and terminal illness affecting nearly 30 million people worldwide. The disease is characterized by the accumulation of fibrous tangles in the brain called amyloid plaques. These fibrillar amyloid plaques aggregate around neurons and blood vessels and restrict blood flow, leading to tissue atrophy and ultimately death. While the cause of AD is not completely understood, strong evidence implicates a 42 amino acid splicing variant of the beta-amyloid precursor protein (APP), Abeta42, as the nucleating factor in the development of plaques. The final cleavage site of APP is a multi-subunit, transmembrane enzyme, the gamma-secretase complex. Elucidation of the gammasecretase complex structure is complicated by its location in the plasma membrane, which prevents crystallographic methods of structure determination. The use of active-site directed affinity probes, though, has been effective in isolation and characterization of the enzyme complex. This thesis details the synthesis and biological evaluation of a series of peptidomimetic transition-state analogs containing Cterminal azide and alkyne functional groups for subsequent use in a Click Chemistry approach to studying the Alzheimer's disease (AD) is an incurable, neurodegenerative, and terminal illness affecting nearly 30 million people worldwide. The disease is characterized by the accumulation of fibrous tangles in the brain called amyloid plaques. These fibrillar amyloid plaques aggregate around neurons and blood vessels and restrict blood flow, leading to tissue atrophy and ultimately death. While the cause of AD is not completely understood, strong evidence implicates a 42 amino acid splicing variant of the beta-amyloid precursor protein (APP), Abeta42, as the nucleating factor in the development of plaques. The final cleavage site of APP is a multi-subunit, transmembrane enzyme, the gamma-secretase complex. Elucidation of the gammasecretase complex structure is complicated by its location in the plasma membrane, which prevents crystallographic methods of structure determination. The use of active-site directed affinity probes, though, has been effective in isolation and characterization of the enzyme complex. This thesis details the synthesis and biological evaluation of a series of peptidomimetic transition-state analogs containing Cterminal azide and alkyne functional groups for subsequent use in a Click Chemistry approach to studying the gamma-secretase complex.

Rights

This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.

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