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, PrP(C), to an abnormal, disease-causing form, PrP(Sc). This paper reports that cyclodextrins have the ability to reduce the pathogenic isoform of the prion protein PrP(Sc) to undetectable levels in scrapie-infected neuroblastoma cells. Beta-cyclodextrin removed PrP(Sc) from the cells at a concentration of 500 microM 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 (IC(50)) for beta-cyclodextrin was 75 microM, whereas alpha-cyclodextrin, which possessed less antiprion activity, had an IC(50) of 750 microM. 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.
Prior
Marguerite
M
School of Biomolecular and Biomedical Science, University College Dublin, Belfield Campus, Dublin 4, Ireland.
Lehmann
Sylvain
S
Sy
Man-Sun
MS
Molloy
Brendan
B
McMahon
Hilary E M
HE
D000818:Animals; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D051379:Mice; D009447:Neuroblastoma; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000472:pathogenicity; D017096:Prion Diseases / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014162:Transfection; D047391:alpha-Cyclodextrins / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
D003505:Cyclodextrins; D018620:PrPSc Proteins; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; C031215:betadex; C032613:alpha-cyclodextrin
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