The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S–20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

中文翻译：

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蛋白酶体组装的小分子调控。

20S蛋白酶体是直接靶向内在无序蛋白（IDP）进行蛋白水解降解的主要蛋白酶。突变，氧化应激或衰老可以诱导IDP的积累，导致错误的信号传导或聚集，这与许多癌症和神经退行性疾病的发病机理有关。因此，促进20S介导的蛋白水解的药物具有许多潜在的治疗应用。我们在此报告了小分子TCH-165对蛋白酶体组装的调节，导致20S水平的增加。游离20S水平的增加对应于IDP的蛋白水解增强，包括α-突触核蛋白，tau，鸟氨酸脱羧酶和c-Fos，但不是结构化蛋白。泛素化蛋白的清除率很大程度上由单个带帽蛋白酶体复合物（19S-20S）维持，但是当所有19S加帽的蛋白酶体复合物都耗尽时，就会发生积累。这项研究说明了一个小分子的第一个例子，该小分子能够通过调节不同蛋白酶体复合物之间的动态平衡来靶向无序蛋白质进行降解。