Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter

Promising treatments for neurogenerative disorders may involve targeting kinetic intermediates, including alpha-synuclein oligomers. Here a kinetic method for quantifying oligomer populations is used to screen small molecule inhibitors of oligomerisation and gain mechanistic insight into their modes of action. The aggregation of alpha-synuclein is a central event in Parkinsons's disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward alpha-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of alpha-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of alpha-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with alpha-synuclein aggregation.