1887

Abstract

At present, there is no effective therapy for any of the neurodegenerative amyloidoses, despite renewed efforts to identify compounds active against the various implicated pathogenetic molecules. We have screened a library of 2960 natural and synthetic compounds in two cell lines chronically infected with mouse prions, and have identified eight new inhibitors of prion replication . They belong to two distinct chemical families that have not previously been recognised as effective in the field of transmissible spongiform encephalopathies: seven are 3-aminosteroids and one is a derivative of erythromycin A with an oxime functionality. Our results suggest that these aminosteroids inhibit prion replication by triggering a common target, possibly implicated in the regulatory pathways of cellular prion protein metabolism. Furthermore, using a quantitative approach for the study of protein stability, it was shown that the erythromycin A derivative altered prion protein stability by direct interaction. Such direct targeting of this amyloid precursor might provide new clues for the understanding of prion diseases and, more importantly, help to define new molecules that are active against prion diseases.

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2009-05-01
2019-11-20
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References

  1. Aguib, Y., Gilch, S., Krammer, C., Ertmer, A., Groschup, M. H. & Schätzl, H. M. ( 2008; ). Neuroendocrine cultured cells counteract persistent prion infection by down-regulation of PrPc. Mol Cell Neurosci 38, 98–109.[CrossRef]
    [Google Scholar]
  2. Bach, S., Talarek, N., Andrieu, T., Vierfond, J. M., Mettey, Y., Galons, H., Dormont, D., Meijer, L., Cullin, C. & Blondel, M. ( 2003; ). Isolation of drugs active against mammalian prions using a yeast-based screening assay. Nat Biotechnol 21, 1075–1081.[CrossRef]
    [Google Scholar]
  3. Bach, S., Tribouillard, D., Talarek, N., Desban, N., Gug, F., Galons, H. & Blondel, M. ( 2006; ). A yeast-based assay to isolate drugs active against mammalian prions. Methods 39, 72–77.[CrossRef]
    [Google Scholar]
  4. Bate, C., Salmona, M., Diomede, L. & Williams, A. ( 2004; ). Squalestatin cures prion-infected neurons and protects against prion neurotoxicity. J Biol Chem 279, 14983–14990.[CrossRef]
    [Google Scholar]
  5. 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.[CrossRef]
    [Google Scholar]
  6. Breydo, L., Bocharova, O. V. & Baskakov, I. V. ( 2005; ). Semiautomated cell-free conversion of prion protein: applications for high-throughput screening of potential antiprion drugs. Anal Biochem 339, 165–173.[CrossRef]
    [Google Scholar]
  7. Brown, P. ( 2007; ). Creutzfeldt–Jakob disease: reflections on the risk from blood product therapy. Haemophilia 13, 33–40.[CrossRef]
    [Google Scholar]
  8. Gilch, S., Winklhofer, K. F., Groschup, M. H., Nunziante, M., Lucassen, R., Spielhaupter, C., Muranyi, W., Riesner, D., Tatzelt, J. & Schätzl, H. M. ( 2001; ). Intracellular re-routing of prion protein prevents propagation of PrPSc and delays onset of prion disease. EMBO J 20, 3957–3966.[CrossRef]
    [Google Scholar]
  9. Gilch, S., Kehler, C. & Schätzl, H. M. ( 2006; ). The prion protein requires cholesterol for cell surface localization. Mol Cell Neurosci 31, 346–353.[CrossRef]
    [Google Scholar]
  10. Gilch, S., Nunziante, M., Ertmer, A. & Schätzl, H. M. ( 2007; ). Strategies for eliminating PrPc as substrate for prion conversion and for enhancing PrPSc degradation. Vet Microbiol 123, 377–386.[CrossRef]
    [Google Scholar]
  11. Goni, F., Prelli, F., Schreiber, F., Scholtzova, H., Chung, E., Kascsak, R., Brown, D. R., Sigurdsson, E. M., Chabalgoity, J. A. & Wisniewski, T. ( 2008; ). High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153, 679–686.[CrossRef]
    [Google Scholar]
  12. Grassi, J., Comoy, E., Simon, S., Créminon, C., Frobert, Y., Trapmann, S., Schimmel, H., Hawkins, S. A., Moynagh, J. & other authors ( 2001; ). Rapid test for the preclinical postmortem diagnosis of BSE in central nervous system tissue. Vet Rec 149, 577–582.[CrossRef]
    [Google Scholar]
  13. Heal, W., Thompson, M. J., Mutter, R., Cope, H., Louth, J. C. & Chen, B. ( 2007; ). Library synthesis and screening: 2,4-diphenylthiazoles and 2,4-diphenyloxazoles as potential novel prion disease therapeutics. J Med Chem 50, 1347–1353.[CrossRef]
    [Google Scholar]
  14. Kawatake, S., Nishimura, Y., Sakaguchi, S., Iwaki, T. & Doh-ura, K. ( 2006; ). Surface plasmon resonance analysis for the screening of anti-prion compounds. Biol Pharm Bull 29, 927–932.[CrossRef]
    [Google Scholar]
  15. Knowles, T. P. & Zahn, R. ( 2006; ). Enhanced stability of human prion proteins with two disulfide bridges. Biophys J 91, 1494–1500.[CrossRef]
    [Google Scholar]
  16. Kocisko, D. A., Baron, G. S., Rubenstein, R., Chen, J., Kuizon, S. & Caughey, B. ( 2003; ). New inhibitors of scrapie-associated prion protein formation in a library of 2000 drugs and natural products. J Virol 77, 10288–10294.[CrossRef]
    [Google Scholar]
  17. Kocisko, D. A., Engel, A. L., Harbuck, K., Arnold, K. M., Olsen, E. A., Raymond, L. D., Vilette, D. & Caughey, B. ( 2005; ). Comparison of protease-resistant prion protein inhibitors in cell cultures infected with two strains of mouse and sheep scrapie. Neurosci Lett 388, 106–111.[CrossRef]
    [Google Scholar]
  18. Livak, K. J. & Schmittgen, T. D. ( 2001; ). Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods 25, 402–408.[CrossRef]
    [Google Scholar]
  19. Lorenzen, S., Dunkel, M. & Preissner, R. ( 2005; ). In silico screening of drug databases for TSE inhibitors. Biosystems 80, 117–122.[CrossRef]
    [Google Scholar]
  20. Magalhães, A. C., Baron, G. S., Lee, K. S., Steele-Mortimer, O., Dorward, D., Prado, M. A. & Caughey, B. ( 2005; ). Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J Neurosci 25, 5207–5216.[CrossRef]
    [Google Scholar]
  21. McCutchen, S. L., Colon, W. & Kelly, J. W. ( 1993; ). Transthyretin mutation Leu-55-Pro significantly alters tetramer stability and increases amyloidogenicity. Biochemistry 32, 12119–12127.[CrossRef]
    [Google Scholar]
  22. Outram, G. W., Dickinson, A. G. & Fraser, H. ( 1974; ). Reduced susceptibility to scrapie in mice after steroid administration. Nature 249, 855–856.[CrossRef]
    [Google Scholar]
  23. Pellarin, R. & Caflisch, A. ( 2006; ). Interpreting the aggregation kinetics of amyloid peptides. J Mol Biol 360, 882–892.[CrossRef]
    [Google Scholar]
  24. Prior, M., Lehmann, S., Sy, M. S., Molloy, B. & McMahon, H. E. ( 2007; ). Cyclodextrins inhibit replication of scrapie prion protein in cell culture. J Virol 81, 11195–11207.[CrossRef]
    [Google Scholar]
  25. Reddy, T. R., Mutter, R., Heal, W., Guo, K., Gillet, V. J., Pratt, S. & Chen, B. ( 2006; ). Library design, synthesis, and screening: pyridine dicarbonitriles as potential prion disease therapeutics. J Med Chem 49, 607–615.[CrossRef]
    [Google Scholar]
  26. Rezaei, H., Marc, D., Choiset, Y., Takahashi, M., Hui Bon Hoa, G., Haertlé, T., Grosclaude, J. & Debey, P. ( 2000; ). High yield purification and physico-chemical properties of full-length recombinant allelic variants of sheep prion protein linked to scrapie susceptibility. Eur J Biochem 267, 2833–2839.[CrossRef]
    [Google Scholar]
  27. Rezaei, H., Choiset, Y., Debey, P., Grosclaude, J. & Haertlé, T. ( 2003; ). Study of stability of variants of ovine prions with different susceptibilities to scrapie. J Therm Anal Calorim 71, 237–247.[CrossRef]
    [Google Scholar]
  28. Ross, C. A. & Poirier, M. A. ( 2004; ). Protein aggregation and neurodegenerative disease. Nat Med 10 (Suppl.), S10–S17.[CrossRef]
    [Google Scholar]
  29. Rothberg, K. G., Ying, Y. S., Kamen, B. A. & Anderson, R. G. ( 1990; ). Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate. J Cell Biol 111, 2931–2938.[CrossRef]
    [Google Scholar]
  30. Schätzl, H. M., Laszlo, L., Holtzman, D. M., Tatzelt, J., DeArmond, S. J., Weiner, R. I., Mobley, W. C. & Prusiner, S. B. ( 1997; ). A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis. J Virol 71, 8821–8831.
    [Google Scholar]
  31. Senisterra, G. A., Soo Hong, B., Park, H. W. & Vedadi, M. ( 2008; ). Application of high-throughput isothermal denaturation to assess protein stability and screen for ligands. J Biomol Screen 13, 337–342.[CrossRef]
    [Google Scholar]
  32. Shyng, S. L., Lehmann, S., Moulder, K. L. & Harris, D. A. ( 1995; ). Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPc, in cultured cells. J Biol Chem 270, 30221–30229.[CrossRef]
    [Google Scholar]
  33. Song, C. H., Furuoka, H., Kim, C. L., Ogino, M., Suzuki, A., Hasebe, R. & Horiuchi, M. ( 2008; ). Effect of intraventricular infusion of anti-prion protein monoclonal antibodies on disease progression in prion-infected mice. J Gen Virol 89, 1533–1544.[CrossRef]
    [Google Scholar]
  34. Stahl, N., Borchelt, D. R., Hsiao, K. & Prusiner, S. B. ( 1987; ). Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 51, 229–240.[CrossRef]
    [Google Scholar]
  35. Stewart, L. A., Rydzewska, L. H., Keogh, G. F. & Knight, R. S. ( 2008; ). Systematic review of therapeutic interventions in human prion disease. Neurology 70, 1272–1281.[CrossRef]
    [Google Scholar]
  36. Tagliavini, F., Forloni, G., Colombo, L., Rossi, G., Girola, L., Canciani, B., Angeretti, N., Giampaolo, L., Peressini, E. & other authors ( 2000; ). Tetracycline affects abnormal properties of synthetic PrP peptides and PrPSc in vitro. J Mol Biol 300, 1309–1322.[CrossRef]
    [Google Scholar]
  37. Taraboulos, A., Scott, M., Semenov, A., Avrahami, D., Laszlo, L. & Prusiner, S. B. ( 1995; ). Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform. J Cell Biol 129, 121–132.[CrossRef]
    [Google Scholar]
  38. Tatzelt, J., Prusiner, S. B. & Welch, W. J. ( 1996; ). Chemical chaperones interfere with the formation of scrapie prion protein. EMBO J 15, 6363–6373.
    [Google Scholar]
  39. Trevitt, C. R. & Collinge, J. ( 2006; ). A systematic review of prion therapeutics in experimental models. Brain 129, 2241–2265.[CrossRef]
    [Google Scholar]
  40. Tucker, S., Ahl, M., Bush, A., Westaway, D., Huang, X. & Rogers, J. T. ( 2005; ). Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5′ untranslated region. Curr Alzheimer Res 2, 249–254.[CrossRef]
    [Google Scholar]
  41. Vey, M., Pilkuhn, S., Wille, H., Nixon, R., DeArmond, S. J., Smart, E. J., Anderson, R. G., Taraboulos, A. & Prusiner, S. B. ( 1996; ). Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains. Proc Natl Acad Sci U S A 93, 14945–14949.[CrossRef]
    [Google Scholar]
  42. Vilette, D., Andreoletti, O., Archer, F., Madelaine, M. F., Vilotte, J. L., Lehmann, S. & Laude, H. ( 2001; ). Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc Natl Acad Sci U S A 98, 4055–4059.[CrossRef]
    [Google Scholar]
  43. Winklhofer, K. F., Hartl, F. U. & Tatzelt, J. ( 2001; ). A sensitive filter retention assay for the detection of PrPSc and the screening of anti-prion compounds. FEBS Lett 503, 41–45.[CrossRef]
    [Google Scholar]
  44. Wuertzer, C. A., Sullivan, M. A., Qiu, X. & Federoff, H. J. ( 2008; ). CNS delivery of vectored prion-specific single-chain antibodies delays disease onset. Mol Ther 16, 481–486.[CrossRef]
    [Google Scholar]
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