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Journal of Virology, October 2007, p. 11195-11207, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.02559-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cyclodextrins Inhibit Replication of Scrapie Prion Protein in Cell Culture{triangledown}

Marguerite Prior,1 Sylvain Lehmann,2 Man-Sun Sy,3 Brendan Molloy,1 and Hilary E. M. McMahon1*

School of Biomolecular and Biomedical Science, University College Dublin, Belfield Campus, Dublin 4, Ireland,1 Institut de Génétique Humaine, CNRS U.P.R. 1142, 141, rue de la Cardonille, 34396 Montpellier Cedex 5, France,2 Case Western Reserve, University School of Medicine, Cleveland, Ohio3

Received 20 November 2006/ Accepted 17 July 2007

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 µM 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 µM, whereas {alpha}-cyclodextrin, which possessed less antiprion activity, had an IC50 of 750 µM. 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.

* Corresponding author. Mailing address: School of Biomolecular and Biomedical Science, University College Dublin, Belfield Campus, Dublin 4, Ireland. Phone: 353 (1) 7162828. Fax: 353 (1) 7161183. E-mail: hilary.mcmahon{at}ucd.ie

{triangledown} Published ahead of print on 15 August 2007.

Journal of Virology, October 2007, p. 11195-11207, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.02559-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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