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Journal of Virology, October 2007, p. 10729-10741, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.01075-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mechanistic Insights into the Cure of Prion Disease by Novel Antiprion Compounds{triangledown}

Sarah Webb,1 Tamuna Lekishvili,1 Corinna Loeschner,1 Shane Sellarajah,2,{dagger} Frances Prelli,3 Thomas Wisniewski,3 Ian H. Gilbert,2,{dagger} and David R. Brown1*

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom,1 Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom,2 Departments of Neurology, Pathology, and Psychiatry, New York University School of Medicine, 550 First Avenue, New York, New York 100163

Received 18 May 2007/ Accepted 11 July 2007

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.

* Corresponding author. Mailing address: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Phone: 44-1225-383133. Fax: 44-1225-386779. E-mail: bssdrb{at}bath.ac.uk

{triangledown} Published ahead of print on 25 July 2007.

{dagger} Present address: Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.

Journal of Virology, October 2007, p. 10729-10741, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.01075-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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