Chemical and Biomolecular Engineering - Theses

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Type: PhD thesis × Subject: atomic force microscopy × Subject: circular dichroism × Author: Ow, Sian-Yang ×

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    Inhibitors of amyloid fibril formation
    Ow, Sian-Yang ( 2013)
    Despite significant recent advances in medical technology, there is still no commercially available treatment for the amyloid diseases that were first observed by Nicolaus Fontanus in 1639. These amyloids are fibrillar aggregates of misfolded proteins that form plaques in various organs and are the hallmarks of a number of incurable diseases such as Alzheimer’s disease and Parkinson’s disease among others. Alzheimer’s disease is the most well-known amyloid disease and was first described by Alois Alzheimer in 1906. It is widely believed that the amyloids or their precursors are responsible for the tissue damage that eventually leads to these diseases, though there is debate in the literature regarding the poor relationship between amount of fibrils and disease progression. Nonetheless, there is a general consensus that the fibrils are related to the progression of these amyloid diseases. Several strategies to prevent or cure amyloid diseases include reducing the amount of amyloid beta (Aβ) produced and the removal of amyloid plaques. Inhibitors that prevent the formation of amyloid fibrils can prevent amyloid diseases from occurring. Hence, this thesis is concerned with the design and testing of amyloid inhibitors as possible therapeutics for these diseases. In order to achieve this objective, the key universal physical properties of amyloid fibrils involved in their self-assembly have been used to design a generic class of fibril inhibitors. A design of an amphiphilic polymer with a hydrophobic backbone and hydrophilic side chains was proposed as a generic amyloid inhibitor and several compounds with this design were obtained. 3 model amyloid forming proteins: bovine insulin (BI), hen egg white lysozyme (HEWL) and Aβ were used to study the effect of these compounds on amyloid fibril formation. Suitable amyloid-forming conditions for these proteins were identified and fibril formation was monitored using Thioflavin T (ThT) fluorescence and other techniques. A naturally occurring compound that fits the proposed inhibitor design was identified and found to be effective at inhibiting amyloid fibril formation in all 3 protein systems. Unusually large fibrils were formed when incubating BI and HEWL with this natural compound and this has potential nanotechnological applications as nanowire templates. To further test the proposed structure, synthetic polymers based on the proposed structure with different chemical groups were produced and one of them, FA-diacid (“FA” was a designation used by the polymer science group of the University of Melbourne for divinylcyclopentane polymers), showed promising inhibitory capabilities. The FA-diacid was improved with the addition of larger hydrophilic side chains to produce the more effective inhibitors named PNGA and PNGE. Finally, glycoproteins based on the structure of AGP were produced and tested using the 3 proteins and were found to have some inhibitory ability. However, they were not as effective as PNGA or PNGE. The results show that compounds with the proposed inhibitor structure can be effective as a generic amyloid inhibitor, but further modification of the current compounds is needed to improve the effectiveness of these compounds as drugs. Further development on this class of chemicals can lead to the production of a new class of generic amyloid inhibitor that can be used to prevent and halt the progression of presently incurable amyloid diseases such as Alzheimer’s disease.