The aggregation of α-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 α-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 α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation.

α-突触核蛋白的聚集是帕金森病和相关突触核蛋白病的核心事件。然而，由于在药理学上以这一过程为目标尚未导致获得批准的疾病缓解治疗，因此开发新的药物发现方法的需求尚未得到满足。在这种情况下，化学动力学的使用最近能够准确量化导致蛋白质错误折叠寡聚体增殖的微观步骤。由于这些物种具有高度神经毒性，有效的治疗策略可能旨在减少它们的数量。在这里，我们利用这种定量方法开发了一种筛选策略，该策略使用对 α-突触核蛋白寡聚体的反应通量作为选择参数。使用这种方法，我们评估了黄酮衍生物库的功效，确定芹菜素是一种同时延迟和减少 α-突触核蛋白寡聚体形成的化合物。这些结果证明了一种基于抑制 α-突触核蛋白寡聚体形成的化合物选择策略，这可能是在与 α-突触核蛋白聚集相关的疾病的药物发现管道中识别小​​分子的关键。