Bach Stéphane, Talarek Nicolas, Andrieu Thibault, Vierfond Jean-Michel, Mettey Yvette, Galons Hervé, Dormont Dominique, Meijer Laurent, Cullin Christophe, Blondel Marc
C.N.R.S., Station Biologique, Cell Cycle Laboratory, place Georges Teissier, 29680 ROSCOFF, Bretagne, France.
Nat Biotechnol. 2003 Sep;21(9):1075-81. doi: 10.1038/nbt855. Epub 2003 Aug 10.
We have developed a rapid, yeast-based, two-step assay to screen for antiprion drugs. The method allowed us to identify several compounds effective against budding yeast prions responsible for the [PSI+] and [URE3] phenotypes. These inhibitors include the kastellpaolitines, a new class of compounds, and two previously known molecules, phenanthridine and 6-aminophenanthridine. Two potent promoters of mammalian prion clearance in vitro, quinacrine and chlorpromazine, which share structural similarities with the kastellpaolitines, were also active in the assay. The compounds isolated here were also active in promoting mammalian prion clearance. These results validate the present method as an efficient high-throughput screening approach to identify new prion inhibitors and furthermore suggest that biochemical pathways controlling prion formation and/or maintenance are conserved from yeast to humans.
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。该方法使我们能够鉴定出几种对导致[PSI+]和[URE3]表型的芽殖酵母朊病毒有效的化合物。这些抑制剂包括一类新的化合物卡斯泰尔泡林碱，以及两种先前已知的分子菲啶和6-氨基菲啶。两种在体外具有强大促进哺乳动物朊病毒清除作用的药物，喹吖因和氯丙嗪，它们与卡斯泰尔泡林碱结构相似，在该检测中也具有活性。在此分离出的化合物在促进哺乳动物朊病毒清除方面也具有活性。这些结果验证了本方法作为一种高效的高通量筛选方法来鉴定新的朊病毒抑制剂，并且进一步表明控制朊病毒形成和/或维持的生化途径从酵母到人类是保守的。
