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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REFERENCE Prions Nature Encyclopaedia of Life Sciences
