Nature Biotechnology
21, 1075 - 1081 (2003)
Published online: 10 August 2003; | doi:10.1038/nbt855
Isolation of drugs active against mammalian prions using a yeast-based
screening assayStéphane Bach1, Nicolas Talarek2, Thibault Andrieu3, Jean-Michel Vierfond4, Yvette Mettey4, Hervé Galons5, Dominique Dormont3, Laurent Meijer1, Christophe Cullin2
& Marc Blondel11
C.N.R.S., Station Biologique, Cell Cycle
Laboratory, place Georges Teissier, 29680 ROSCOFF, Bretagne,
France. 2
IBGC, 1 rue Camille Saint-Saens,
33077 Bordeaux Cedex, France. 3
Service de Neurovirologie, CEA/CRSSA/EPHE, BP
6, 92265 Fontenay aux Roses Cedex,
France. 4
Faculté de Médecine et de Pharmacie,
34 rue du Jardin des Plantes, BP 199, 86005
Poitiers Cedex, France. 5
Laboratoire de Chimie Organique 2,
Université René Descartes, 4 avenue de
l'Observatoire, 75270 Paris Cedex 06,
France.
Correspondence should be addressed to Marc Blondel blondel@sb-roscoff.fr.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.
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