This Article Full Text Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kocisko, D. A. Articles by Caughey, B. Search for Related Content PubMed PubMed Citation Articles by Kocisko, D. A. Articles by Caughey, B.

New Inhibitors of Scrapie-Associated Prion Protein Formation in a Library of 2,000 Drugs and Natural Products

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana,¹ Laboratory of Molecular and Biochemical Neurovirology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York,² Chengdu Jinniu Institute, Food Bureau of Sichuan Province, Chengdu Sichuan, China³

Received 14 April 2003/ Accepted 25 June 2003

Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases associated with the accumulation of a disease-specific form of prion protein (PrP) in the brain. One approach to TSE therapeutics is the inhibition of PrP accumulation. Indeed, many inhibitors of the accumulation of PrP associated with scrapie (PrP^Sc) in scrapie-infected mouse neuroblastoma cells (ScN₂a) also have antiscrapie activity in rodents. To expedite the search for potential TSE therapeutic agents, we have developed a high-throughput screening assay for PrP^Sc inhibitors using ScN₂a cells in a 96-well format. A library of 2,000 drugs and natural products was screened in ScN₂a cells infected with scrapie strain RML (Chandler) or 22L. Forty compounds were found to have concentrations causing 50% inhibition (IC₅₀s) of PrP^Sc accumulation of 10 µM against both strains. Seventeen had IC₅₀s of 1 µM against both strains. Several classes of compounds were represented in the 17 most potent inhibitors, including naturally occurring polyphenols (e.g., tannic acid and tea extracts), phenothiazines, antihistamines, statins, and antimalarial compounds. These 17 compounds were also evaluated in a solid-phase cell-free hamster PrP conversion assay. Only the polyphenols inhibited the cell-free reaction, and their IC₅₀s were near 100 nM. Several of the new PrP^Sc inhibitors cross the blood-brain barrier and thus have potential to be effective after TSE infection reaches the brain. The fact that many are either approved human drugs or edible natural products should facilitate their use in animal testing and clinical trials.

This article has been cited by other articles:

• Brown, P. (2008). Transmissible spongiform encephalopathy in the 21st century: Neuroscience for the clinical neurologist. Neurology 70: 713-722 [Full Text]  
• Abbas, S., Bhoumik, A., Dahl, R., Vasile, S., Krajewski, S., Cosford, N. D.P., Ronai, Z. A. (2007). Preclinical Studies of Celastrol and Acetyl Isogambogic Acid in Melanoma. Clin. Cancer Res. 13: 6769-6778 [Abstract] [Full Text]  
• Pani, A., Norfo, C., Abete, C., Mulas, C., Putzolu, M., Laconi, S., Orru, C. D., Cannas, M. D., Vascellari, S., La Colla, P., Dessi, S. (2007). Antiprion Activity of Cholesterol Esterification Modulators: a Comparative Study Using Ex Vivo Sheep Fibroblasts and Lymphocytes and Mouse Neuroblastoma Cell Lines. Antimicrob. Agents Chemother. 51: 4141-4147 [Abstract] [Full Text]  
• Caughey, W. S., Priola, S. A., Kocisko, D. A., Raymond, L. D., Ward, A., Caughey, B. (2007). Cyclic Tetrapyrrole Sulfonation, Metals, and Oligomerization in Antiprion Activity. Antimicrob. Agents Chemother. 51: 3887-3894 [Abstract] [Full Text]  
• Webb, S., Lekishvili, T., Loeschner, C., Sellarajah, S., Prelli, F., Wisniewski, T., Gilbert, I. H., Brown, D. R. (2007). Mechanistic Insights into the Cure of Prion Disease by Novel Antiprion Compounds. J. Virol. 81: 10729-10741 [Abstract] [Full Text]  
• Kuwata, K., Nishida, N., Matsumoto, T., Kamatari, Y. O., Hosokawa-Muto, J., Kodama, K., Nakamura, H. K., Kimura, K., Kawasaki, M., Takakura, Y., Shirabe, S., Takata, J., Kataoka, Y., Katamine, S. (2007). Hot spots in prion protein for pathogenic conversion. Proc. Natl. Acad. Sci. USA 104: 11921-11926 [Abstract] [Full Text]  
• Kocisko, D. A., Caughey, B., Morrey, J. D., Race, R. E. (2006). Enhanced antiscrapie effect using combination drug treatment.. Antimicrob. Agents Chemother. 50: 3447-3449 [Abstract] [Full Text]  
• Trevitt, C. R, Collinge, J. (2006). A systematic review of prion therapeutics in experimental models. Brain 129: 2241-2265 [Abstract] [Full Text]  
• Kocisko, D. A., Vaillant, A., Lee, K. S., Arnold, K. M., Bertholet, N., Race, R. E., Olsen, E. A., Juteau, J.-M., Caughey, B. (2006). Potent Antiscrapie Activities of Degenerate Phosphorothioate Oligonucleotides. Antimicrob. Agents Chemother. 50: 1034-1044 [Abstract] [Full Text]  
• Baron, G. S., Magalhaes, A. C., Prado, M. A. M., Caughey, B. (2006). Mouse-Adapted Scrapie Infection of SN56 Cells: Greater Efficiency with Microsome-Associated versus Purified PrP-res. J. Virol. 80: 2106-2117 [Abstract] [Full Text]  
• May, B. C.H., Govaerts, C., Cohen, F. E. (2006). Developing therapeutics for the diseases of protein misfolding. Neurology 66: S118-S122 [Abstract] [Full Text]  
• Raymond, G. J., Olsen, E. A., Lee, K. S., Raymond, L. D., Bryant, P. K. III, Baron, G. S., Caughey, W. S., Kocisko, D. A., McHolland, L. E., Favara, C., Langeveld, J. P. M., van Zijderveld, F. G., Mayer, R. T., Miller, M. W., Williams, E. S., Caughey, B. (2006). Inhibition of Protease-Resistant Prion Protein Formation in a Transformed Deer Cell Line Infected with Chronic Wasting Disease. J. Virol. 80: 596-604 [Abstract] [Full Text]  
• Kocisko, D. A., Caughey, B. (2006). Mefloquine, an Antimalaria Drug with Antiprion Activity In Vitro, Lacks Activity In Vivo. J. Virol. 80: 1044-1046 [Abstract] [Full Text]  
• Bertsch, U., Winklhofer, K. F., Hirschberger, T., Bieschke, J., Weber, P., Hartl, F. U., Tavan, P., Tatzelt, J., Kretzschmar, H. A., Giese, A. (2005). Systematic Identification of Antiprion Drugs by High-Throughput Screening Based on Scanning for Intensely Fluorescent Targets. J. Virol. 79: 7785-7791 [Abstract] [Full Text]  
• Feraudet, C., Morel, N., Simon, S., Volland, H., Frobert, Y., Creminon, C., Vilette, D., Lehmann, S., Grassi, J. (2005). Screening of 145 Anti-PrP Monoclonal Antibodies for Their Capacity to Inhibit PrPSc Replication in Infected Cells. J. Biol. Chem. 280: 11247-11258 [Abstract] [Full Text]  
• Taniguchi, S., Suzuki, N., Masuda, M., Hisanaga, S.-i., Iwatsubo, T., Goedert, M., Hasegawa, M. (2005). Inhibition of Heparin-induced Tau Filament Formation by Phenothiazines, Polyphenols, and Porphyrins. J. Biol. Chem. 280: 7614-7623 [Abstract] [Full Text]  
• Kocisko, D. A., Morrey, J. D., Race, R. E., Chen, J., Caughey, B. (2004). Evaluation of new cell culture inhibitors of protease-resistant prion protein against scrapie infection in mice. J. Gen. Virol. 85: 2479-2483 [Abstract] [Full Text]  
• Cordeiro, Y., Lima, L. M. T. R., Gomes, M. P. B., Foguel, D., Silva, J. L. (2004). Modulation of Prion Protein Oligomerization, Aggregation, and {beta}-sheet Conversion by 4,4'-Dianilino-1,1'-binaphthyl-5,5'-sulfonate (bis-ANS). J. Biol. Chem. 279: 5346-5352 [Abstract] [Full Text]