Date of Award

6-1-2012

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Marianna Torok

Second Advisor

Bela Torok

Third Advisor

Deyang Qu

Abstract

Amyloid-beta self-assembly is the central event in the pathology of the Alzheimer's disease (AD), which is one of the most prevalent neurodegenerative disorders. The complexity of amyloid beta self-assembly lies in the involvement of multiple pathways and assembly intermediates, including oligomers, protofibrils, and other soluble aggregates. In the traditional amyloid cascade hypothesis of AD the fibrils are associated with pathology; while recent studies also emphasize the highly neurotoxic nature of oligomers, which, in fact, are suggested being the most important link to neurotoxicity. Therefore, the inhibition of amyloid beta self-assembly, both at the fibril and oligomeric stage complimented by the disassembly of the preformed aggregates have become imperative and is among the promising therapeutic options. Although several small molecules are reported in literature that inhibits the in vitro formation of amyloid fibrils or oligomers, these studies are not systematic regarding the chemical nature of the inhibitors. This current work aims at filling the gap that exists in understanding the type of interactions that occur between inhibitor and amyloid beta peptide. It has been focused on finding the structural features of the active molecules which can specifically target the process of fibrillogenesis or the more toxic oligomeric species. The structure activity relationship studies of different groups of around 185 structurally diverse molecules have been carried out in order to identify the most significant features required for successful amyloid beta self-assembly inhibition. The design of these groups is based on combining the primary structural motifs responsible for the activity of known inhibitors in different pathological pathways of AD. The inhibitor candidates have been tested in multiple assays, including the inhibition of amyloid beta; fibrillogenesis and oligomer formation and the reverse processes i.e. the disassembly of preformed fibrils and oligomers. In addition the molecules have also been tested for their free radical scavenging capacity and in improving the cholinergic deficit associated with the disease. The work has resulted in the determination of several core fragments required for efficient binding of the small molecules to amyloid beta. Design of new lead compounds active in multiple targeted pathways have been accomplished providing a platform for further drug development against AD.

Comments

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