1887

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Volume 90, Issue 6

Proof of concept for the reduction of classical swine fever infection in pigs by a novel viral polymerase inhibitor Free

Abstract

5-[(4-Bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP) is a representative of a class of imidazopyridines with potent antiviral activity against pestiviruses including classical swine fever virus (CSFV). This study analysed whether the lead compound, BPIP, was able to reduce virus replication in infected piglets. The compound, administered in feed, was readily bioavailable and was well tolerated. Eight specific-pathogen-free pigs received a daily dose of 75 mg kg (mixed in feed) for a period of 15 consecutive days, starting 1 day before infection with the CSFV field isolate Wingene. BPIP-treated pigs developed a short, transient viraemia (one animal remained negative) and leukopenia (three animals did not develop leukopenia). Virus titres at peak viraemia (7 days post-infection) were markedly lower (∼1000-fold) than in untreated animals (=0.00005) and the viral genome load in blood was also significantly lower (≤0.001) in drug-treated animals than in untreated animals over the entire experiment. At the end of the experiment (day 33), no infectious virus was detectable in the tonsils of BPIP-treated animals, although low levels of viral RNA were detected. The inability to isolate infectious virus from the tonsils indicates that the risk of a persistent CSFV infection is negligible. Further optimization of the antiviral potency and bioavailability of this lead compound may result in molecules completely suppressing virus replication. A potent antiviral could potentially be used as a primary control measure against virus spread in case of an outbreak, in addition to present countermeasures. This study provides the first proof of concept for the prophylaxis/treatment of CSFV infection in pigs.

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2009-06-01
2024-04-20
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References

  1. Ahrens U., Kaden V., Drexler C., Visser N. 2000; Efficacy of the classical swine fever (CSF) marker vaccine Porcilis pesti in pregnant sows. Vet Microbiol 77:83–97 [CrossRef]
     [Google Scholar]
  2. Beer M., Reimann I., Hoffmann B., Depner K. 2007; Novel marker vaccines against classical swine fever. Vaccine 25:5665–5670 [CrossRef]
     [Google Scholar]
  3. Depner K. R., Bouma A., Koenen F., Klinkenberg D., Lange E., de Smit H., Vanderhallen H. 2001; Classical swine fever (CSF) marker vaccine. Trial II. Challenge study in pregnant sows. . Vet Microbiol 83:107–120 [CrossRef]
     [Google Scholar]
  4. de Smit A. J., Bouma A., de Kluijver E. P., Terpstra C., Moormann R. J. 2001a; Duration of the protection of an E2 subunit marker vaccine against classical swine fever after a single vaccination. Vet Microbiol 78:307–317 [CrossRef]
     [Google Scholar]
  5. de Smit A. J., Bouma A., van Gennip H. G., de Kluijver E. P., Moormann R. J. 2001b; Chimeric (marker) C-strain viruses induce clinical protection against virulent classical swine fever virus (CSFV) and reduce transmission of CSFV between vaccinated pigs. Vaccine 19:1467–1476 [CrossRef]
     [Google Scholar]
  6. Dewulf J., Laevens H., Koenen F., Vanderhallen H., Mintiens K., Deluyker H., de Kruif A. 2000; An experimental infection with classical swine fever in E2 sub-unit marker-vaccine vaccinated and in non-vaccinated pigs. Vaccine 19:475–482 [CrossRef]
     [Google Scholar]
  7. Dewulf J., Laevens H., Koenen F., Mintiens K., de Kruif A. 2001; An E2 sub-unit marker vaccine does not prevent horizontal or vertical transmission of classical swine fever virus. Vaccine 20:86–91 [CrossRef]
     [Google Scholar]
  8. Dewulf J., Laevens H., Koenen F., Mintiens K., de Kruif A. 2004; Efficacy of E2-sub-unit marker and C-strain vaccines in reducing horizontal transmission of classical swine fever virus in weaner pigs. Prev Vet Med 65:121–133 [CrossRef]
     [Google Scholar]
  9. Dewulf J., Koenen F., Ribbens S., Haegeman A., Laevens H., De Kruif A. 2005; Evaluation of the epidemiological importance of classical swine fever infected, E2 sub-unit marker vaccinated animals with RT-nPCR positive blood samples. J Vet Med B Infect Dis Vet Public Health 52:367–371 [CrossRef]
     [Google Scholar]
  10. Floegel-Niesmann G., Bunzenthal C., Fischer S., Moennig V. 2003; Virulence of recent and former classical swine fever virus isolates evaluated by their clinical and pathological signs. J Vet Med B Infect Dis Vet Public Health 50:214–220 [CrossRef]
     [Google Scholar]
  11. Grubman M. J. 2005; Development of novel strategies to control foot-and-mouth disease: marker vaccines and antivirals. Biologicals 33:227–234 [CrossRef]
     [Google Scholar]
  12. Haegeman A., Dewulf J., Vrancken R., Tignon M., Ribbens S., Koenen F. 2006; Characterisation of the discrepancy between PCR and virus isolation in relation to classical swine fever virus detection. J Virol Methods 136:44–50 [CrossRef]
     [Google Scholar]
  13. Holm-Jensen M. 1981; Detection of antibodies against hog cholera virus and bovine viral diarrhoea in porcine serum. A comparative examination using CF, PLA, and NPLA assay. Acta Vet Scan 22:85–98
     [Google Scholar]
  14. Koenig P., Hoffmann B., Depner K. R., Reimann I., Teifke J. P., Beer M. 2007; Detection of classical swine fever vaccine virus in blood and tissue samples of pigs vaccinated either with a conventional C-strain vaccine or a modified live marker vaccine. Vet Microbiol 120:343–351 [CrossRef]
     [Google Scholar]
  15. Le Dimna M., Vrancken R., Koenen F., Bougeard S., Mesplede A., Hutet E., Kuntz-Simon G., Le Potier M.-F. 2008; Validation of two commercial real-time RT-PCR kits for rapid and specific diagnosis of classical swine fever virus. J Virol Methods 147:136–142 [CrossRef]
     [Google Scholar]
  16. Le Potier M.-F., Mesplède A., Vannier P. 2006; Classical swine fever and other pestiviruses. In Diseases of Swine , 9th edn. pp 309–322Edited by Straw B. E., Zimmerman J. J., D'Allaire S., Taylor. Ames: IA; Blackwell Publishing;
     [Google Scholar]
  17. Paeshuyse J., Leyssen P., Mabery E., Boddeker N., Vrancken R., Froeyen M., Ansari I. H., Dutartre H., Rozenski J. other authors 2006; A novel, highly selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase. J Virol 80:149–160 [CrossRef]
     [Google Scholar]
  18. Paton D. J., McGoldrick A., Bensaude E., Belak S., Mittelholzer C., Koenen F., Vanderhallen H., Greiser-Wilke I., Scheibner H. other authors 2000; Classical swine fever virus: a second ring test to evaluate RT-PCR detection methods. Vet Microbiol 77:71–81 [CrossRef]
     [Google Scholar]
  19. Puerstinger G., Paeshuyse J., Herdewijn P., Rozenski J., De Clercq E., Neyts J. 2006; Substituted 5-benzyl-2-phenyl-5H-imidazo[4,5-c]pyridines: a new class of pestivirus inhibitors. Bioorg Med Chem Lett 16:5345–5349 [CrossRef]
     [Google Scholar]
  20. Puerstinger G., Paeshuyse J., De Clercq E., Neyts J. 2007a; Antiviral 2,5-disubstituted imidazo[4,5-c]pyridines: from anti-pestivirus to anti-hepatitis C virus activity. Bioorg Med Chem Lett 17:390–393 [CrossRef]
     [Google Scholar]
  21. Puerstinger G., Paeshuyse J., Heinrich S., Mohr J., Schraffl N., De Clercq E., Neyts J. 2007b; Antiviral 2,5-disubstituted imidazo[4,5-c]pyridines: further optimization of anti-hepatitis C virus activity. Bioorg Med Chem Lett 17:5111–5114 [CrossRef]
     [Google Scholar]
  22. Rozen S., Skaletsky H. 2000; Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
     [Google Scholar]
  23. Sharpe K., Gibbens J., Morris H., Drew T. 2001; Epidemiology of the 2000 CSF outbreak in East Anglia: preliminary findings. Vet Rec 148:91
     [Google Scholar]
  24. Stegeman A., Elbers A., de Smit H., Moser H., Smak J., Pluimers F. 2000; The 1997–1998 epidemic of classical swine fever in The Netherlands. Vet Microbiol 73:183–196 [CrossRef]
     [Google Scholar]
  25. Suradhat S., Intrakamhaeng M., Damrongwatanapokin S. 2001; The correlation of virus-specific interferon- γ production and protection against classical swine fever virus infection. Vet Immunol Immunopathol 83:177–189 [CrossRef]
     [Google Scholar]
  26. Tignon M., Kulcsár G., Belak S., Haegeman A., Barna T., Fábián K., Lévai R., Farsang A., Van Der Stede Y. other authors 2008; Application of a commercial real-time RT-PCR assay for surveillance of classical swine fever: evaluation by testing sequential tissue and blood samples. Open Vet Sci J 2:104–110 [CrossRef]
     [Google Scholar]
  27. Uttenthal A., Le Potier M.-F., Romero L., De Mia G. M., Floegel-Niesmann G. 2001; Classical swine fever (CSF) marker vaccine. Trial I. Challenge studies in weaner pigs. Vet Microbiol 83:85–106 [CrossRef]
     [Google Scholar]
  28. Vanderhallen H., Mittelholzer C., Hofmann M. A., Koenen F. 1999; Classical swine fever virus is genetically stable in vitro and in vivo . Arch Virol 144:1669–1677 [CrossRef]
     [Google Scholar]
  29. van Oirschot J. T. 2003; Vaccinology of classical swine fever: from lab to field. Vet Microbiol 96:367–384 [CrossRef]
     [Google Scholar]
  30. Vliegen I., Paeshuyse J., De Burghgraeve T., Lehman L. S., Paulson M., Shih I.-H., Mabery E., Boddeker N., Reiser H. other authors 2009; Substituted imidazopyridines as potent inhibitors of HCV replication. J Hepatol 26 Feb; Epub ahead of print
    [Google Scholar]
  31. Voigt H., Merant C., Wienhold D., Braun A., Hutet E., Le Potier M.-F., Saalmuller A., Pfaff E., Buttner M. 2007; Efficient priming against classical swine fever with a safe glycoprotein E2 expressing Orf virus recombinant (ORFV VrV-E2). Vaccine 25:5915–5926 [CrossRef]
     [Google Scholar]
  32. Vrancken R., Paeshuyse J., Haegeman A., Puerstinger G., Froeyen M., Herdewijn P., Kerkhofs P., Neyts J., Koenen F. 2008; Imidazo[4,5-c]pyridines inhibit the in vitro replication of the classical swine fever virus and target the viral polymerase. Antiviral Res 77:114–119 [CrossRef]
     [Google Scholar]
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Proof of concept for the reduction of classical swine fever infection in pigs by a novel viral polymerase inhibitor
J. Gen. Virol. 90, 1335 (2009); https://doi.org/10.1099/vir.0.008839-0
/content/journal/jgv/10.1099/vir.0.008839-0
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