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Development of inhibitors of amyloid fibril formation
Priss, Anastasiia ; Yushchenko, Dmytro (advisor) ; Schneider, Bohdan (referee) ; Hudeček, Jiří (referee)
α-Synuclein (α-Syn) is a small neuronal protein that is present in synapses, and, presumably, regulates the vesicle-mediated neurotransmitter release. Misfolding of α-Syn into amyloid fibrils is linked to the progression of synucleinopathies, including Parkinson's disease, the second most common neurodegenerative disorder. To date, no Parkinson's disease treatment that stops or retards neurodegeneration was established. Several direct and indirect approaches of influence on the α-Syn aggregation are extensively developed in search of potential drug candidates. Recently proposed inhibition of the α-Syn fibrils growth by blocking their ends is one of the most promising known strategies, as it opens an opportunity to design fibrillization inhibitors that act at very low concentrations. However, rational design of inhibitors of this type was not performed yet. The ultimate goal of this work was the development of highly efficient and specific inhibitors of α-Syn fibrillization. Therefore, careful structure-activity relationship analysis of the fibril end blocking inhibitors was performed and the affinity to fibril end was defined as the crucial factor for their inhibition activity. Using the recent data on the fibril structure, we designed inhibitors that are able to bind to the fibril ends with...
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