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Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-10-23 , DOI: 10.1016/j.chembiol.2019.10.004
Zhiqiang Du 1 , Stephanie Valtierra 1 , Luzivette Robles Cardona 1 , Sara Fernandez Dunne 2 , Chi-Hao Luan 2 , Liming Li 1
Affiliation  

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.

中文翻译:

使用新建立的酵母高通量筛选系统鉴定抗pr病毒化合物。

on病毒样蛋白质聚集是人类致命的一组神经退行性疾病的病理学基础,包括阿尔茨海默氏病(AD),帕金森氏病,肌萎缩性侧索硬化症和可传播的海绵状脑病。目前,很少有高通量筛选(HTS)系统可用于抗-病毒小分子鉴定。在这里,我们描述了一种在酵母中创新的表型HTS系统,该系统可有效鉴定消除酵母pr病毒[SWI +]的化合物。我们表明,某些已确定的抗[SWI +]化合物可以破坏其他非[SWI +] pr病毒的稳定性,并且它们的拮抗作用可能是specific病毒和/或变体特异性的。有趣的是 在确定的命中因素中,有几种先前确定的抗PrPSc化合物以及美国食品药品监督管理局批准的用于AD治疗的药物,验证了此HTS系统的功效。而且,一些命中可以降低由几种致病性哺乳动物蛋白的表达诱导的蛋白毒性。因此,我们已经建立了有用的HTS系统,用于识别可能拮抗蛋白化和人类蛋白病的化合物。
更新日期:2019-11-09
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