1887

Abstract

The accumulation of PrP, the protease-resistant abnormal form of the host-encoded cellular prion protein, PrP, plays a central role in transmissible spongiform encephalopathies. Human contamination by bovine spongiform encephalopathy (BSE) has propelled many scientific teams on a highway for anti-prion drug development. This study reports that heparan sulfate mimetics (HMs), developed originally for their effect on tissue regeneration, abolish prion propagation in scrapie-infected GT1 cells. PrP does not reappear for up to 50 days post-treatment. When tested , one of these compounds, HM2602, hampered PrP accumulation in scrapie- and BSE-infected mice and prolonged significantly the survival time of 263K scrapie-infected hamsters. Interestingly, HM2602 is an apparently less toxic and more potent inhibitor of PrP accumulation than dextran sulfate 500, a molecule known to exhibit anti-prion properties . Kinetics of PrP disappearance and unaffected PrP levels during treatment suggest that HMs are able to block the conversion of PrP into PrP. It is speculated that HMs act as competitors of endogenous heparan sulfates known to act as co-receptors for the prion protein. Since these molecules are particularly amenable to drug design, their anti-prion potential could be developed further and optimized for the treatment of prion diseases.

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2003-09-01
2024-12-14
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References

  1. Adjou K. T., Demaimay R., Lasmézas C., Deslys J. P., Seman M., Dormont D. 1995; MS-8209, a new amphotericine B derivative, provides enhanced efficacy in delaying hamster scrapie. Antimicrob Agents Chemother 39:2810–2812
    [Google Scholar]
  2. Adjou K. T., Demaimay R., Lasmézas C. I., Seman M., Deslys J. P., Dormont D. 1996; Differential effects of a new amphotericin B derivative, MS-8209, on mouse BSE and scrapie: implications for the mechanism of action of polyene antibiotics. Res Virol 147:213–218
    [Google Scholar]
  3. Barret A., Tagliavini F., Forloni G. 13 other authors 2003; Evaluation of quinacrine treatment for prion diseases. J Virol (in Press)
    [Google Scholar]
  4. Beringue V., Adjou K. T., Lamoury F., Maignien T., Deslys J. P., Race R., Dormont D. 2000; Opposite effects of dextran sulfate 500, the polyene antibiotic MS-8209, and Congo red on accumulation of the protease-resistant isoform of PrP in the spleens of mice inoculated intraperitoneally with the scrapie agent. J Virol 74:5432–5440
    [Google Scholar]
  5. Bernfield M., Gotte M., Park P. W., Reizes O., Fitzgerald M. L., Lincecum J., Zako M. 1999; Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777
    [Google Scholar]
  6. Bolton D. C., McKinley M. P., Prusiner S. B. 1982; Identification of a protein that purifies with the scrapie prion. Science 218:1309–1311
    [Google Scholar]
  7. Brimacombe D. B., Bennett A. D., Wusteman F. S., Gill A. G., Dann J. C., Bostock C. J. 1999; Characterization and polyanion-binding properties of purified recombinant prion protein. Biochem J 342:605–613
    [Google Scholar]
  8. Caughey B., Raymond G. J. 1993; Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. J Virol 67:643–650
    [Google Scholar]
  9. Caughey B., Race R. E., Ernst D., Buchmeier M. J., Chesebro B. 1989; Prion protein (PrP) biosynthesis in scrapie-infected and uninfected neuroblastoma cells. J Virol 63:175–181
    [Google Scholar]
  10. Desgranges P., Barbaud C., Caruelle J. P., Barritault D., Gautron J. 1999; A substituted dextran enhances muscle fiber survival and regeneration in ischemic and denervated rat EDL muscle. FASEB J 13:761–766
    [Google Scholar]
  11. Deslys J.-P., Beringue V., Lasmézas C. 1998; Method for screening substances with therapeutical action in the treatment of transmissible spongiform encephalopathy. Europe Commissariat à l'Energie Atomique patent no. EP1998000902078
    [Google Scholar]
  12. Diringer H., Ehlers B. 1991; Chemoprophylaxis of scrapie in mice. J Gen Virol 72:457–460
    [Google Scholar]
  13. Ehlers B., Diringer H. 1984; Dextran sulphate 500 delays and prevents mouse scrapie by impairment of agent replication in spleen. J Gen Virol 65:1325–1330
    [Google Scholar]
  14. Farquhar C. F., Dickinson A. G. 1986; Prolongation of scrapie incubation period by an injection of dextran sulphate 500 within the month before or after infection. J Gen Virol 67:463–473
    [Google Scholar]
  15. Farquhar C., Dickinson A., Bruce M. 1999; Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies. Lancet 353:117
    [Google Scholar]
  16. Fraser H. 1976; The pathology of natural and experimental scrapie. In Slow Virus Diseases of Animals and Man pp  267–305 Edited by Kimberlin R. H. New York: North-Holland;
    [Google Scholar]
  17. Gabizon R., Meiner Z., Halimi M., Ben-Sasson S. A. 1993; Heparin-like molecules bind differentially to prion-proteins and change their intracellular metabolic fate. J Cell Physiol 157:319–325
    [Google Scholar]
  18. Gauczynski S., Peyrin J. M., Haik S. 8 other authors 2001; The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J 20:5863–5875
    [Google Scholar]
  19. Ghani A. C., Ferguson N. M., Donnelly C. A., Anderson R. M. 2000; Predicted vCJD mortality in Great Britain. Nature 406:583–584
    [Google Scholar]
  20. Ghani A. C., Donnelly C. A., Ferguson N. M., Anderson R. M. 2002; The transmission dynamics of BSE and vCJD. C R Acad Sci III 325:37–47
    [Google Scholar]
  21. 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
    [Google Scholar]
  22. Gonzalez-Iglesias R., Pajares M. A., Ocal C., Espinosa J. C., Oesch B., Gasset M. 2002; Prion protein interaction with glycosaminoglycan occurs with the formation of oligomeric complexes stabilized by CuII bridges. J Mol Biol 319:527–540
    [Google Scholar]
  23. Grassi J., Comoy E., Simon S. 8 other authors 2001; Rapid test for the preclinical postmortem diagnosis of BSE in central nervous system tissue. Vet Rec 149:577–582
    [Google Scholar]
  24. Hill A. F., Joiner S., Linehan J., Desbruslais M., Lantos P. L., Collinge J. 2000; Species-barrier-independent prion replication in apparently resistant species. Proc Natl Acad Sci U S A 97:10248–10253
    [Google Scholar]
  25. Hundt C., Peyrin J. M., Haik S. 8 other authors 2001; Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptor. EMBO J 20:5876–5886
    [Google Scholar]
  26. Kimberlin R. H., Walker C. A. 1977; Characteristics of a short incubation model of scrapie in the golden hamster. J Gen Virol 34:295–304
    [Google Scholar]
  27. Kimberlin R. H., Walker C. A. 1986; Suppression of scrapie infection in mice by heteropolyanion 23, dextran sulfate, and some other polyanions. Antimicrob Agents Chemother 30:409–413
    [Google Scholar]
  28. 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
    [Google Scholar]
  29. Ladogana A., Casaccia P., Ingrosso L., Cibati M., Salvatore M., Xi Y. G., Mascullo C., Pocchiari M. 1992; Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. J Gen Virol 73:661–665
    [Google Scholar]
  30. Lasmézas C. I., Deslys J. P., Demaimay R., Adjou K. T., Hauw J. J., Dormont D. 1996; Strain specific and common pathogenic events in murine models of scrapie and bovine spongiform encephalopathy. J Gen Virol 77:1601–1609
    [Google Scholar]
  31. Lasmézas C. I., Deslys J. P., Robain O. 7 other authors 1997; Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275:402–405
    [Google Scholar]
  32. Lee D. C., Stenland C. J., Hartwell R. C. 7 other authors 2000; Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 84:77–89
    [Google Scholar]
  33. Leucht C., Simoneau S., Rey C., Vana K., Rieger R., Lasmézas C. I., Weiss S. 2003; The 37 kDa/67 kDa laminin receptor is required for PrPSc propagation in scrapie-infected neuronal cells. EMBO Rep 4:290–295 erratum 4, 439
    [Google Scholar]
  34. Mange A., Nishida N., Milhavet O., McMahon H. E., 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
    [Google Scholar]
  35. 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
    [Google Scholar]
  36. Meddahi A., Bree F., Papy-Garcia D., Gautron J., Barritault D., Caruelle J. P. 2002; Pharmacological studies of RGTA(11), a heparan sulfate mimetic polymer, efficient on muscle regeneration. J Biomed Mater Res 62:525–531
    [Google Scholar]
  37. Merlini G., Ascari E., Amboldi N. other authors 1995; Interaction of the anthracycline 4′-iodo-4′-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci U S A 92:2959–2963
    [Google Scholar]
  38. Peretz D., Williamson R. A., Kaneko K. 10 other authors 2001; Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412:739–743
    [Google Scholar]
  39. Petit E., Papy Garcia D., Barbier Chassefiere V. 2002; Procédé de sulfonation de composés comprenant des groupements hydroxyle (OH) libres ou des amines primaires ou secondaires OTR3. Patent no: FR2832708
    [Google Scholar]
  40. Prusiner S. B. 1982; Novel proteinaceous infectious particles cause scrapie. Science 216:136–144
    [Google Scholar]
  41. Prusiner S. B., McKinley M. P., Bowman K. A., Bolton D. C., Bendheim P. E., Groth D. F., Glenner G. G. 1983; Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 35:349–358
    [Google Scholar]
  42. Race R., Raines A., Raymond G. J., Caughey B., Chesebro B. 2001; Long-term subclinical carrier state precedes scrapie replication and adaptation in a resistant species: analogies to bovine spongiform encephalopathy and variant Creutzfeldt–Jakob disease in humans. J Virol 75:10106–10112
    [Google Scholar]
  43. Race R., Meade-White K., Raines A., Raymond G. J., Caughey B., Chesebro B. 2002; Subclinical scrapie infection in a resistant species: persistence, replication, and adaptation of infectivity during four passages. J Infect Dis 186 (Suppl. 2):S166–S170
    [Google Scholar]
  44. Safar J., Wille H., Itri V., Groth D., Serban H., Torchia M., Cohen F. E., Prusiner S. B. 1998; Eight prion strains have PrPSc molecules with different conformations. Nat Med 4:1157–1165
    [Google Scholar]
  45. 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]
  46. 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
    [Google Scholar]
  47. Supattapone S., Wille H., Uyechi L., Safar J., Tremblay P., Szoka F. C., Cohen F. E., Prusiner S. B., Scott M. R. 2001; Branched polyamines cure prion-infected neuroblastoma cells. J Virol 75:3453–3461
    [Google Scholar]
  48. Tagliavini F., McArthur R. A., Canciani B. 18 other authors 1997; Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science 276:1119–1122
    [Google Scholar]
  49. Turnbull J., Powell A., Guimond S. 2001; Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends Cell Biol 11:75–82
    [Google Scholar]
  50. Warner R. G., Hundt C., Weiss S., Turnbull J. E. 2002; Identification of the heparan sulfate binding sites in the cellular prion protein. J Biol Chem 277:18421–18430
    [Google Scholar]
  51. 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
    [Google Scholar]
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