Mechanistic Insights into the Cure of Prion Disease by Novel Antiprion Compounds.
From: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
Journal of virology
- Publish Date: Oct 2007
- ISSN: 0022-538X
- Volume: 81
- Issue: 19
- Pages: 10729-41
- Medium: Print
- Language: English
- Citation (JAMA): Webb Sarah, Lekishvili Tamuna, Loeschner Corinna, et al. Mechanistic Insights into the Cure of Prion Disease by Novel Antiprion Compounds.. J. Virol. Oct 2007;81:10729-41
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.
Mesh Headings (Keywords): Animals, Benzene Derivatives, Biphenyl Compounds, Cell Membrane, Cells, Cultured, Congo Red, Mice, Mice, Inbred Strains, Oxidation-Reduction, PrPSc Proteins, Prion Diseases, Scrapie
Check for Full Text / PubMed Unique Identifier (PMID): 17652397
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