1887

Abstract

Over the last 30 years, many drugs have been tested both in cell culture and for their ability to prevent the generation of prions and the development of transmissible spongiform encephalopathies. Among the compounds tested, dendrimers are defined by their branched and repeating molecular structure. The anti-prion activity of new cationic phosphorus-containing dendrimers (P-dendrimers) with tertiary amine end-groups was tested. These molecules had a strong anti-prion activity, decreasing both PrP and infectivity in scrapie-infected cells at non-cytotoxic doses. They can bind PrP and decrease the amount of pre-existing PrP from several prion strains, including the BSE strain. More importantly, when tested in a murine scrapie model, the dendrimers were able to decrease PrP accumulation in the spleen by more than 80 %. These molecules have a high bio-availability and therefore exhibit relevant potential for prion therapeutics for at least post-exposure prophylaxis.

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2004-06-01
2019-10-23
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References

  1. Aguzzi, A., Glatzel, M., Montrasio, F., Prinz, M. & Heppner, F. L. ( 2001; ). Interventional strategies against prion diseases. Nat Rev Neurosci 2, 745–749.[CrossRef]
    [Google Scholar]
  2. Barret, A., Tagliavini, F., Forloni, G. & 13 other authors ( 2003; ). Evaluation of quinacrine treatment for prion diseases. J Virol 3, 8462–8469.
    [Google Scholar]
  3. Béranger, F., Mangé, A., Solassol, J. & Lehmann, S. ( 2001; ). Cell culture models of transmissible spongiform encephalopathies. Biochem Biophys Res Commun 289, 311–316.[CrossRef]
    [Google Scholar]
  4. Beringue, V., Lamoury, F., Adjou, K. T., Maignien, T., Demoy, M., Couvreur, P. & Dormont, D. ( 2000; ). Pharmacological manipulation of early PrPres accumulation in the spleen of scrapie-infected mice. Arch Virol Suppl, 39–56.
    [Google Scholar]
  5. Bosque, P. J. & Prusiner, S. B. ( 2000; ). Cultured cell sublines highly susceptible to prion infection. J Virol 74, 4377–4386.[CrossRef]
    [Google Scholar]
  6. Bourne, N., Stanberry, L. R., Kern, E. R., Holan, G., Matthews, B. & Bernstein, D. I. ( 2000; ). Dendrimers, a new class of candidate topical microbicides with activity against herpes simplex virus infection. Antimicrob Agents Chemother 44, 2471–2474.[CrossRef]
    [Google Scholar]
  7. Brown, P. ( 2002; ). Drug therapy in human and experimental transmissible spongiform encephalopathy. Neurology 58, 1720–1725.[CrossRef]
    [Google Scholar]
  8. Bruce, M. E., Brown, K. L., Mabbott, N. A., Farquhar, C. F. & Jeffrey, M. ( 2000; ). Follicular dendritic cells in TSE pathogenesis. Immunol Today 21, 442–446.[CrossRef]
    [Google Scholar]
  9. Caughey, W. S., Raymond, L. D., Horiuchi, M. & Caughey, B. ( 1998; ). Inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines. Proc Natl Acad Sci U S A 95, 12117–12122.[CrossRef]
    [Google Scholar]
  10. Collinge, J. ( 2001; ). Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24, 519–550.[CrossRef]
    [Google Scholar]
  11. Demart, S., Fournier, J. G., Creminon, C. & 7 other authors ( 1999; ). New insight into abnormal prion protein using monoclonal antibodies. Biochem Biophys Res Commun 265, 652–657.[CrossRef]
    [Google Scholar]
  12. Gilch, S., Winklhofer, K. F., Groschup, M. H. & 7 other authors ( 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]
  13. Heppner, F. L., Musahl, C., Arrighi, I., Klein, M. A., Rulicke, T., Oesch, B., Zinkernagel, R. M., Kalinke, U. & Aguzzi, A. ( 2001; ). Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294, 178–182.[CrossRef]
    [Google Scholar]
  14. Klohn, P. C., Stoltze, L., Flechsig, E., Enari, M. & Weissmann, C. ( 2003; ). A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc Natl Acad Sci U S A 100, 11666–11671.[CrossRef]
    [Google Scholar]
  15. Korth, C., May, B. C., Cohen, F. E. & Prusiner, S. B. ( 2001; ). Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A 98, 9836–9841.[CrossRef]
    [Google Scholar]
  16. Lasmezas, C. I., Cesbron, J. Y., Deslys, J. P., Demaimay, R., Adjou, K. T., Rioux, R., Lemaire, C., Locht, C. & Dormont, D. ( 1996; ). Immune system-dependent and -independent replication of the scrapie agent. J Virol 70, 1292–1295.
    [Google Scholar]
  17. Lehmann, S. & Harris, D. A. ( 1995; ). A mutant prion protein displays an aberrant membrane association when expressed in cultured cells. J Biol Chem 270, 24589–24597.[CrossRef]
    [Google Scholar]
  18. Lehmann, S., Laude, H., Harris, D. A., Carp, C., Vilette, D., Katamine, S., Madec, J. Y. & Nishida, N. ( 2001; ). Ex vivo transmission of mouse adapted prion strains to N2a and GT1-7 cell lines. In Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics, pp. 679–686. Edited by K. Iqbal, S. S. Sisodia & B. Wingblad. Chichester, UK: Wiley.
  19. Loup, C., Zanta, M. A., Caminade, A. M., Majoral, J. P. & Meunier, B. ( 1999; ). Preparation of water-soluble cationic phosphorus-containing dendrimers as DNA transfecting agents. Chem Eur J 5, 3644–3650.[CrossRef]
    [Google Scholar]
  20. Mabbott, N. A., Young, J., McConnell, I. & Bruce, M. E. ( 2003; ). Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol 77, 6845–6854.[CrossRef]
    [Google Scholar]
  21. Malik, N., Wiwattanapatapee, R., Klopsch, R., Lorenz, K., Frey, H., Weener, J. W., Meijer, E. W., Paulus, W. & Duncan, R. ( 2000; ). Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. J Control Release 65, 133–148.[CrossRef]
    [Google Scholar]
  22. Mangé, A., Nishida, N., Milhavet, O., McMahon, H. E. M., Casanova, D. & Lehmann, S. ( 2000; ). Amphotericin B inhibits the generation of the scrapie isoform of the prion protein in infected cultures. J Virol 74, 3135–3140.[CrossRef]
    [Google Scholar]
  23. May, B. C., Fafarman, A. T., Hong, S. B., Rogers, M., Deady, L. W., Prusiner, S. B. & Cohen, F. E. ( 2003; ). Potent inhibition of scrapie prion replication in cultured cells by bis-acridines. Proc Natl Acad Sci U S A 100, 3416–3421.[CrossRef]
    [Google Scholar]
  24. Meyer, R. K., McKinley, M. P., Bowman, K. A., Braunfeld, M. B., Barry, R. A. & Prusiner, S. B. ( 1986; ). Separation and properties of cellular and scrapie prion proteins. Proc Natl Acad Sci U S A 83, 2310–2314.[CrossRef]
    [Google Scholar]
  25. Nishida, N., Tremblay, P., Sugimoto, T. & 12 other authors ( 1999; ). A mouse prion protein transgene rescues mice deficient for the prion protein gene from Purkinje cell degeneration and demyelination. Lab Invest 79, 689–697.
    [Google Scholar]
  26. Nishida, N., Harris, D. A., Vilette, D., Laude, H., Frobert, Y., Grassi, J., Casanova, D., Milhavet, O. & Lehmann, S. ( 2000; ). Successful transmission of three mouse-adapted scrapie strains to murine neuroblastoma cell lines overexpressing wild-type mouse prion protein. J Virol 74, 320–325.[CrossRef]
    [Google Scholar]
  27. Nishikawa, K., Matsuoka, K., Kita, E. & 12 other authors ( 2002; ). A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157 : H7. Proc Natl Acad Sci U S A 99, 7669–7674.[CrossRef]
    [Google Scholar]
  28. Padilla De Jesus, O. L., Ihre, H. R., Gagne, L., Frechet, J. M. & Szoka, F. C., Jr ( 2002; ). Polyester dendritic systems for drug delivery applications: in vitro and in vivo evaluation. Bioconjug Chem 13, 453–461.[CrossRef]
    [Google Scholar]
  29. Priola, S. A. & Caughey, B. ( 1994; ). Inhibition of scrapie-associated PrP accumulation. Probing the role of glycosaminoglycans in amyloidogenesis. Mol Neurobiol 8, 113–120.[CrossRef]
    [Google Scholar]
  30. Priola, S. A., Raines, A. & Caughey, W. S. ( 2000; ). Porphyrin and phthalocyanine anti-scrapie compounds. Science 287, 1503–1506.[CrossRef]
    [Google Scholar]
  31. Prusiner, S. B. ( 1982; ). Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144.[CrossRef]
    [Google Scholar]
  32. Sethi, S., Lipford, G., Wagner, H. & Kretzschmar, H. ( 2002; ). Post-exposure prophylaxis against prion disease with a stimulator of innate immunity. Lancet 360, 229–230.[CrossRef]
    [Google Scholar]
  33. Supattapone, S., Nguyen, H. O., Cohen, F. E., Prusiner, S. B. & Scott, M. R. ( 1999; ). Elimination of prions by branched polyamines and implications for therapeutics. Proc Natl Acad Sci U S A 96, 14529–14534.[CrossRef]
    [Google Scholar]
  34. Vincent, L., Varet, J., Pille, J. Y. & 9 other authors ( 2003; ). Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis: in vitro and in vivo studies. Int J Cancer 105, 419–429.[CrossRef]
    [Google Scholar]
  35. Will, R. G., Ironside, J. W., Zeidler, M. & 7 other authors ( 1996; ). A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347, 921–925.[CrossRef]
    [Google Scholar]
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