Cyclodextrins inhibit replication of scrapie prion protein in cell culture

Prion diseases are fatal neurodegenerative disorders that are caused by the conversion of a normal host-encoded protein, PrPC, to an abnormal, disease-causing form, PrPSc. This paper reports that cyclodextrins have the ability to reduce the pathogenic isoform of the prion protein PrPSc to undetectable levels in scrapie-infected neuroblastoma cells. Beta-cyclodextrin removed PrPSc from the cells at a concentration of 500 RM following 2 weeks of treatment. Structure activity studies revealed that antiprion activity was dependent on the size of the cyclodextrin. The half-maximal inhibitory concentration (IC50) for beta-cyclodextrin was 75 mu M, whereas a-cyclodextrin, which possessed less antiprion activity, had an IC50 of 750 mu M. This report presents cyclodextrins as a new class of antiprion compound. For decades, the pharmaceutical industry has successfully used cyclodextrins for their complex-forming ability; this ability is due to the structural orientation of the glucopyranose units, which generate a hydrophobic cavity that can facilitate the encapsulation of hydrophobic moieties. Consequently, cyclodextrins could be ideal candidates for the treatment of prion diseases.