Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System
Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System
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DOI：
10.1016/j.chembiol.2019.10.004
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发表时间：
2019-12-19
影响因子：
8.6
通讯作者：
Li, Liming
中科院分区：
文献类型：
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作者：
Du, Zhiqiang;Valtierra, Stephanie;Li, Liming
朊病毒样蛋白聚集是人类致命的神经退行性疾病的病理基础，包括阿尔茨海默病（AD）、帕金森病、肌萎缩侧索硬化症和传染性海绵状脑病。目前，很少有高通量筛选（HTS）系统可用于抗朊病毒小分子鉴定。在这里，我们描述了酵母中的一种创新表型 HTS 系统，该系统可以有效识别消除酵母朊病毒 [SWI+] 的化合物。我们表明，一些已鉴定的抗[SWI+]化合物可以破坏其他非[SWI+]朊病毒的稳定性，并且它们的拮抗作用可以是朊病毒和/或变体特异性的。有趣的是，在已确定的热门药物中，有几种先前确定的抗 PrPSc 化合物和美国食品和药物管理局批准的几种用于 AD 治疗的药物，验证了该 HTS 系统的功效。此外，一些命中可以减少由几种致病性哺乳动物蛋白表达诱导的蛋白毒性。因此，我们建立了一个有用的 HTS 系统，用于识别可能对抗朊病毒和人类蛋白质病的化合物。
Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI+]. We show that some identified anti-[SWI+] compounds can destabilize other non-[SWI+] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrPSc compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.