Dipartimento di Scienze Chimiche, Università degli Studi di Catania, viale A. Doria 6, 95125, Catania, Italy.
Eur J Med Chem. 2019 Apr 1;167:10-36. doi: 10.1016/j.ejmech.2019.01.045. Epub 2019 Jan 28.
A host of human diseases, including Parkinson's disease and Dementia with Lewy bodies, are suspected to be directly linked to protein aggregation. Amyloid protein aggregates and oligomeric intermediates of α-synuclein are observed in synucleinopathies and considered to be mediators of cellular toxicity. Hence, α-synuclein has seen as one of the leading and most compelling targets and is receiving a great deal of attention from researchers. Nevertheless, there is no neuroprotective approach directed toward Parkinson's disease or other synucleinopathies so far. In this review, we summarize the available data concerning inhibitors of α-synuclein aggregation and their advancing towards clinical use. The compounds are grouped according to their chemical structures, providing respective insights into their mechanism of action, pharmacology, and pharmacokinetics. Overall, shared structure-activity elements are emerging, as well as specific binding modes related to the ability of the modulators to establish hydrophobic and hydrogen bonds interactions with the protein. Some molecules with encouraging in vivo data support the possibility of translation to the clinic.
许多人类疾病，包括帕金森病和路易体痴呆症，都被怀疑与蛋白质聚集直接相关。在突触核蛋白病中观察到淀粉样蛋白聚集物和α-突触核蛋白的寡聚中间体，被认为是细胞毒性的介质。因此，α-突触核蛋白被视为主要和最有说服力的靶点之一，受到研究人员的高度关注。然而，到目前为止，还没有针对帕金森病或其他突触核蛋白病的神经保护方法。在这篇综述中，我们总结了有关α-突触核蛋白聚集抑制剂及其向临床应用进展的现有数据。根据化合物的化学结构对其进行分组，分别介绍了它们的作用机制、药理学和药代动力学。总的来说，正在出现共同的结构-活性要素，以及与调节剂与蛋白质建立疏水和氢键相互作用的能力相关的特定结合模式。一些具有令人鼓舞的体内数据的分子支持将其转化为临床应用的可能性。
