Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small molecules have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compounds and discuss how these chemical chaperones hold great promise to alter the course of PD progression.

帕金森病 (PD) 的特征是多巴胺能神经元的进行性丧失和大脑中 α-突触核蛋白 (α-syn) 沉积物的积累。α-syn 聚集在 PD 中的关键作用使其成为潜在的疾病修饰疗法的有吸引力的目标。然而，蛋白质的无序性质、其多步聚集机制以及中间物种结构信息的缺乏使 α-syn 淀粉样蛋白沉积调节剂的发现复杂化。尽管存在这些困难，小分子已被证明可以阻止 α-syn 的错误折叠和聚集，甚至可以解开成熟的 α-syn 淀粉样原纤维。在这篇综述中，我们提供了这些主要小化合物的最新概述，并讨论了这些化学伴侣如何有望改变 PD 进展过程。