Isolation of drugs active against mammalian prions using a yeast-based screening assay.
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.
Bach
Stéphane
S
C.N.R.S., Station Biologique, Cell Cycle Laboratory, place Georges Teissier, 29680 ROSCOFF, Bretagne, France.
Talarek
Nicolas
N
Andrieu
Thibault
T
Vierfond
Jean-Michel
JM
Mettey
Yvette
Y
Galons
Hervé
H
Dormont
Dominique
D
Meijer
Laurent
L
Cullin
Christophe
C
Blondel
Marc
M
D000818:Animals; D045744:Cell Line, Tumor; D015169:Colony Count, Microbial / Q000379:methods; D006801:Humans; D008322:Mammals; D051379:Mice; D009447:Neuroblastoma; D010617:Phenanthridines / Q000737:chemistry* / Q000302:isolation & purification* / Q000378:metabolism; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D025941:Protein Interaction Mapping / Q000379:methods*; D012441:Saccharomyces cerevisiae / Q000145:classification / Q000302:isolation & purification* / Q000378:metabolism*; D013045:Species Specificity; D015003:Yeasts / Q000145:classification / Q000302:isolation & purification / Q000378:metabolism
D010617:Phenanthridines; D011328:Prions