Synucleinopathies are a group of disorders characterized by the accumulation of α-Synuclein amyloid inclusions in the brain. Preventing α-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q α-Synuclein variants in vitro and interferes with α-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed α-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson’s Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of α-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.

中文翻译：

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用极简化合物 ZPDm 抑制 α-突触核蛋白聚集和成熟原纤维分解

突触核蛋白病是一组以α-突触核蛋白淀粉样蛋白包裹体在大脑中积聚为特征的疾病。由于蛋白质的无序性质和原纤维生成的随机性质，防止 α-突触核蛋白聚集具有挑战性，但同时，它是对这些病理进行治疗干预的一种有前途的方法。一项高通量筛选计划使我们能够发现 ZPDm，这是 14,000 多种化合物库中最小的活性分子。尽管 ZPDm 结构与之前描述的 ZPD-2 聚集抑制剂的结构高度相关，但我们在这里表明它们的作用机制完全不同。ZPDm 抑制野生型 A30P 的聚集，和 H50Q α-Synuclein 变体体外并干扰蛋白质错误折叠循环扩增测定中的 α-Synuclein 种子聚集。然而，ZPDm 的显着特点是其强大的拆除预先形成的 α-突触核蛋白淀粉样蛋白原纤维的效力。对帕金森病秀丽隐杆线虫模型的研究证明，这些体外特性转化为 ZPDm 治疗动物中 α-突触核蛋白内含物积累的显着减少。与以前的数据一起，目前的工作说明了常见分子支架顶部的不同化学基团如何导致不同但互补的抗淀粉样蛋白活性。证明这些体外特性转化为 ZPDm 治疗动物中 α-突触核蛋白内含物积累的显着减少。与以前的数据一起，目前的工作说明了常见分子支架顶部的不同化学基团如何导致不同但互补的抗淀粉样蛋白活性。证明这些体外特性转化为 ZPDm 治疗动物中 α-突触核蛋白内含物积累的显着减少。与以前的数据一起，目前的工作说明了常见分子支架顶部的不同化学基团如何导致不同但互补的抗淀粉样蛋白活性。