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Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK1
Institute for Animal Health, Compton Laboratories, Compton, Newbury, Berks RG20 7NN, UK2
Author for correspondence: James Hope. Fax +44 1635 577263. e-mail james.hope{at}bbsrc.ac.uk
Transmissible spongiform encephalopathies (TSEs) are incurable, fatal diseases. The dye Congo Red (CR) can cure cells infected with agents of the sheep TSE, scrapie, but is not used as a therapeutic or prophylactic agent in vivo, as its effects are small, possibly due to low blood–brain barrier permeability, and complicated by its intrinsic carcinogenicity. In this paper, the development is described of a structure–activity profile for CR by testing a series of analogues of this dye for their ability to inhibit the formation of the protease-resistant prion protein, PrP-res, a molecular marker for the infectious agent, in the scrapie-infected, SMB cell line. It was found that the central benzidine unit in CR, which gives the molecule potential carcinogenicity, can be replaced by other, less toxic moieties and that the sulphonate groups on the core molecule can be replaced by carboxylic acids, which should improve the brain permeability of these compounds. However, detailed dose–response curves were generated for several derivatives and they revealed that, while some compounds showed inhibition of PrP-res accumulation at high concentrations, at low concentrations they actually stimulated levels of PrP-res above control values.
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