Mechanistic insights into the cure of prion disease by novel antiprion compounds

Sarah Webb, Tamuna Lekishvili, Corinna Loeschner, Shane Sellarajah, Frances Prelli, Thomas Wisniewski, Ian H. Gilbert, David R. Brown

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    19 Citations (Scopus)

    Abstract

    Prion diseases are fatal neurodegenerative disorders. Identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. Congo red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. Congo red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain barrier. We have prepared two Congo red derivatives, designed without these liabilities, with potent activity in cellular models of prion disease. One of these compounds cured cells of the transmissible agent. The mechanism of action of these compounds is possibly multifactorial. The high affinity of Congo red derivatives, including compounds that are ineffective and are effective at the cure of prion disease, for abnormally folded prion protein suggests that the amyloidophylic property of these derivatives is not as critical to the mechanism of action as other effects. Congo red derivatives that are effective at the cure of prion disease increased the degradation of abnormal PrP by the proteasome. Therefore, the principal mechanism of action of the Congo red analogues was to prevent inhibition of proteasomal activity by PrPSc.

    Original languageEnglish
    Pages (from-to)10729-10741
    Number of pages13
    JournalJournal of Virology
    Volume81
    Issue number19
    DOIs
    Publication statusPublished - Oct 2007

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