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The design, synthesis, and evaluation of compounds that bind to Alzheimer's-related and HIV-1-related amyloids

  • Author(s): Capule, Christina Cecilia
  • et al.
Abstract

Amyloids--misfolded, aggregated peptides--have been implicated in over thirty human diseases. This thesis focused on the study of two different amyloids--A[beta](1- 42) and SEVI (semen-derived enhancer of virus infection)-- associated with two distinct conditions--Alzheimer's Disease (AD) and Acquired Immune Deficiency Syndrome (AIDS), respectively. A[beta] aggregates are a hallmark of AD and may play a central, causative role in the pathogenesis of this disease. A[beta]-amyloid-targeting small molecules have, therefore, attracted wide interest as potential agents for the treatment or diagnosis of AD. This thesis describes the development of a general method to evaluate small molecule-A[beta]-amyloid binding interactions via a modified quantitative ELISA protocol. The implementation of an in vitro model to evaluate the blood-brain barrier permeability of [beta]-amyloid- targeting compounds is also discussed in this thesis. The design and evaluation of a new class of fluorescent probes that bind to A[beta] aggregates is described in this thesis. The advantage of these compounds is that their spectroscopic properties can be altered and fine-tuned via simple synthetic methods. The second portion of this thesis discusses the study of small molecules that bind to SEVI, a naturally abundant amyloid found in semen. SEVI can potentially increase the infectivity of HIV-1 in cells by up to 400,000-fold. Although the mechanism of SEVI- mediated transmission of HIV-1 remains poorly understood, evidence suggests that SEVI binds to both HIV-1 virions and cell membranes, thereby facilitating viral infection. We hypothesized that BTA-EG₆, a derivative of the well- known amyloid-binding compound Thioflavin T, could coat SEVI fibrils, thereby inhibit HIV-1 interactions with SEVI fibrils, and thus, reduce SEVI-mediated enhancement of HIV -1 infectivity. The results of these investigations are presented in this thesis. The final project described in this thesis is the design, synthesis, and evaluation of multivalent analogs of BTA-EG6. The goals of this project were 2-fold : 1) Create compounds that bind with high affinity to both A[beta] fibrils and SEVI fibrils based on the multivalent design strategy and 2) evaluate whether oligomers of the BTA moiety exhibit improved ability over the BTA monomer to inhibit SEVI-mediated enhancement of HIV-1 infectivity. The results of this project are presented in this thesis

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