α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs’ membrane permeabilization activity. The most effective aggregation inhibitors were derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide. They interacted strongly with the N-terminal part of monomeric αSN and reduced αSO-membrane interactions, possibly by affecting electrostatic interactions. Several compounds reduced αSO toxicity toward neuronal cell lines. The inhibitors introduced chemical modifications of αSN that were, however, not a prerequisite for inhibitory activity. We also identified several phenyl-benzoxazol compounds that promoted αSN aggregation (proaggregators). These compounds may be useful tools to modulate αSN aggregationin cellula.

中文翻译：

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通过高通量筛选确定的有效α-突触核蛋白聚集抑制剂主要针对单体状态

α-突触核蛋白（αSN）聚集对于帕金森氏病（PD）的病因至关重要。随机筛选αSN聚集和检测早期低聚物（αSOs）的困难，对化合物的大规模筛选以鉴定聚集抑制剂具有挑战性。我们开发了一种高通量筛选测定法，将SDS刺激的αSN聚集与FRET结合使用，可重现性地检测αSN聚集的初始阶段。我们筛选了746,000种化合物，导致58个命中明显抑制αSN聚集并降低αSOs的膜通透活性。最有效的聚集抑制剂是（4-羟基萘-1-基）磺酰胺的衍生物。它们可能与单体αSN的N末端部分强烈相互作用，并可能通过影响静电相互作用而降低了αSO-膜相互作用。几种化合物可降低αSO对神经元细胞系的毒性。抑制剂引入了αSN的化学修饰，但是，这不是抑制活性的先决条件。我们还确定了几种促进αSN聚集的苯基苯并恶唑化合物（聚集剂）。这些化合物可能是调节纤维素中αSN聚集的有用工具。