Tribouillard Déborah, Bach Stéphane, Gug Fabienne, Desban Nathalie, Beringue Vincent, Andrieu Thibault, Dormont Dominique, Galons Hervé, Laude Hubert, Vilette Didier, Blondel Marc
CNRS UMR7150, Amyloids and Cell Division Cycle Laboratory, Station Biologique, Roscoff, Bretagne, France.
Biotechnol J. 2006 Jan;1(1):58-67. doi: 10.1002/biot.200500001.
Prions are misfolded proteins capable of propagating their altered conformation which are commonly considered as the causative agent of transmissible spongiform encephalopathies, a class of fatal neurodegenerative diseases. Currently, no treatment for prion-based diseases is available. Recently we have developed a rapid, yeast-based, two-step assay to screen for anti-prion drugs [1]. This new method allowed us to identify several compounds that are effective in vivo against budding yeast [PSI+] and [URE3] prions but also able to promote mammalian prion clearance in three different cell culture-based assays. Taken together, these results validate our method as an economic and efficient high-throughput screening approach to identify novel prion inhibitors or to carry on comprehensive structure-activity studies for already isolated anti-mammalian prion drugs. These results suggest furthermore that biochemical pathways controlling prion formation and/or maintenance are conserved from yeast to human and thus amenable to pharmacological and genetic analysis. Finally, it would be very interesting to test active drugs isolated using the yeast-based assay in models for other diseases (neurodegenerative or not) involving amyloid fibers like Huntington's, Parkinson's or Alzheimer's diseases.
朊病毒是能够传播其改变的构象的错误折叠蛋白，通常被认为是传染性海绵状脑病的病原体，这是一类致命的神经退行性疾病。目前，尚无针对朊病毒相关疾病的治疗方法。最近，我们开发了一种基于酵母的快速两步检测法来筛选抗朊病毒药物[1]。这种新方法使我们能够鉴定出几种在体内对出芽酵母[PSI+]和[URE3]朊病毒有效的化合物，而且在三种不同的基于细胞培养的检测中也能够促进哺乳动物朊病毒的清除。综上所述，这些结果验证了我们的方法是一种经济高效的高通量筛选方法，可用于鉴定新型朊病毒抑制剂或对已分离的抗哺乳动物朊病毒药物进行全面的构效关系研究。这些结果还表明，控制朊病毒形成和/或维持的生化途径从酵母到人类都是保守的，因此适合进行药理学和遗传学分析。最后，在涉及淀粉样纤维的其他疾病（神经退行性疾病或非神经退行性疾病）模型中，如亨廷顿舞蹈症、帕金森病或阿尔茨海默病，测试使用基于酵母的检测法分离出的活性药物将会非常有趣。
