Antiprion action of new cyclodextrin analogues.
BACKGROUND
Prion disorders are characterised by the accumulation of a misfolded isoform (PrPSc) of the host encoded prion protein (PrPC). This paper examines the antiprion potential of cyclodextrin (CD) analogues and it identifies sulphated-beta-cyclodextrin, with a half-maximal inhibitory concentration (IC50) of 2.4 microM, as having 31-fold greater antiprion activity than that previously reported for beta-cyclodextrin (betaCD).


METHODS
Scrapie infected cells were treated with a range of betaCD analogues. This enabled a CD structure to antiprion activity analysis to be carried out. The metachromatic activity of each of the cyclodextrins was determined, this test is employed to mimic complexation of glycosaminogylcans to a cell membrane.


RESULTS
Sulphated-betaCD had an IC50 of 2.4 microM and it was the only CD found to have metachromatic activity. Its activity was equivalent to that of heparin and heparin sulphate, this may account for sulphated-betaCD's superior antiprion action.


CONCLUSIONS
In solution heparin can form a helical structure with a hydrophobic interior, the hydrophobic interior of cyclic CDs is vital for CD molecule encapsulation. The controlled CD structure, however, restricts degradation by human enzymes; consequently sulphated-CDs could be ideal candidates in the search for prion therapeutics. Sulphated-CDs may open up avenues for the treatment of TSEs.
McEvoy
Karl
K
Prion Research Group, UCD School of Biomolecular and Biomedical Science, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
McMahon
Hilary E M
HE
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000494:pharmacology
D000925:Anticoagulants; D003505:Cyclodextrins; D018620:PrPSc Proteins; D013431:Sulfates; D047392:beta-Cyclodextrins; D006493:Heparin; C031215:betadex