Skip to content
1887

Journal of General Virology header logo Journal of General Virology

Volume 91, Issue 11

A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection No Access

Abstract

Enviroxime is an anti-enterovirus compound that targets viral protein 3A and/or 3AB and suppresses a replication step of enterovirus by an unknown mechanism. To date, a number of anti-enterovirus compounds that have little structural similarity to enviroxime but induce common resistance mutations in the 3A-encoding region have been identified. The present study identified a novel type of functionally enviroxime-like compound, AN-12-H5. This compound had no structural similarity to enviroxime or to known enviroxime-like compounds, including TTP-8307, GW5074 and Flt3 Inhibitor II. A resistance phenotype of poliovirus (PV) to these compounds was conferred by a major enviroxime-resistance mutation of PV (G5318A, 3A-Ala70Thr), but not by resistance mutations to guanidine hydrochloride and brefeldin A. AN-12-H5 had a common structure with the anti-enterovirus 71 (EV71) compound AN-23-F6. AN-12-H5 and AN-23-F6 inhibited an early stage of EV71 infection after virus binding to the cells. Mutations in capsid proteins (G3112A, VP1-Ala224Thr, and G2396A, VP3-Arg227Lys mutations) were determined as resistant mutations to AN-12-H5 and AN-23-F6 in the early stage of EV71 infection. These results suggest that AN-12-H5 is a bifunctional anti-enterovirus compound that belongs to a novel class of enviroxime-like compounds and targets both a replication step and an early stage of EV71 infection.

  • Received:
  • Accepted:
  • Published Online:
© SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.023374-0
2010-11-01
2025-03-23
Loading full text...

Full text loading...

References

  1. Abdel-Rahman, S. M. & Kearns, G. L.(1998). Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution and effect of food. Antimicrob Agents Chemother 42, 2706–2709. [Google Scholar]
  2. Arita, M., Zhu, S. L., Yoshida, H., Yoneyama, T., Miyamura, T. & Shimizu, H.(2005). A Sabin 3-derived poliovirus recombinant contained a sequence homologous with indigenous human enterovirus species C in the viral polymerase coding region. J Virol 79, 12650–12657.[CrossRef] [Google Scholar]
  3. Arita, M., Nagata, N., Sata, T., Miyamura, T. & Shimizu, H.(2006). Quantitative analysis of poliomyelitis-like paralysis in mice induced by a poliovirus replicon. J Gen Virol 87, 3317–3327.[CrossRef] [Google Scholar]
  4. Arita, M., Ami, Y., Wakita, T. & Shimizu, H.(2008a). Cooperative effect of the attenuation determinants derived from poliovirus Sabin 1 strain is essential for attenuation of enterovirus 71 in the NOD/SCID mouse infection model. J Virol 82, 1787–1797.[CrossRef] [Google Scholar]
  5. Arita, M., Wakita, T. & Shimizu, H.(2008b). Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity. J Gen Virol 89, 2518–2530.[CrossRef] [Google Scholar]
  6. Arita, M., Wakita, T. & Shimizu, H.(2009). Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime. J Gen Virol 90, 1869–1879.[CrossRef] [Google Scholar]
  7. Baltera, R. F., Jr & Tershak, D. R.(1989). Guanidine-resistant mutants of poliovirus have distinct mutations in peptide 2C. J Virol 63, 4441–4444. [Google Scholar]
  8. Barnard, D. L.(2006). Current status of anti-picornavirus therapies. Curr Pharm Des 12, 1379–1390.[CrossRef] [Google Scholar]
  9. Barton, D. J. & Flanegan, J. B.(1997). Synchronous replication of poliovirus RNA: initiation of negative-strand RNA synthesis requires the guanidine-inhibited activity of protein 2C. J Virol 71, 8482–8489. [Google Scholar]
  10. Belov, G. A., Feng, Q., Nikovics, K., Jackson, C. L. & Ehrenfeld, E.(2008). A critical role of a cellular membrane traffic protein in poliovirus RNA replication. PLoS Pathog 4, e1000216.[CrossRef] [Google Scholar]
  11. Benton, P. A., Barrett, D. J., Matts, R. L. & Lloyd, R. E.(1996). The outcome of poliovirus infections in K562 cells is cytolytic rather than persistent after hemin-induced differentiation. J Virol 70, 5525–5532. [Google Scholar]
  12. Bienz, K., Egger, D., Troxler, M. & Pasamontes, L.(1990). Structural organization of poliovirus RNA replication is mediated by viral proteins of the P2 genomic region. J Virol 64, 1156–1163. [Google Scholar]
  13. Bodian, D.(1949). Histopathologic basis of clinical findings in poliomyelitis. Am J Med 6, 563–578.[CrossRef] [Google Scholar]
  14. Brown-Augsburger, P., Vance, L. M., Malcolm, S. K., Hsiung, H., Smith, D. P. & Heinz, B. A.(1999). Evidence that enviroxime targets multiple components of the rhinovirus 14 replication complex. Arch Virol 144, 1569–1585.[CrossRef] [Google Scholar]
  15. Caliguiri, L. A. & Tamm, I.(1968). Action of guanidine on the replication of poliovirus RNA. Virology 35, 408–417.[CrossRef] [Google Scholar]
  16. Carp, R. I.(1981). Persistent infection of human lymphoid cells with poliovirus and development of temperature-sensitive mutants. Intervirology 15, 49–56.[CrossRef] [Google Scholar]
  17. Chang, L. Y., Lin, T. Y., Hsu, K. H., Huang, Y. C., Lin, K. L., Hsueh, C., Shih, S. R., Ning, H. C., Hwang, M. S. & other authors(1999). Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet 354, 1682–1686.[CrossRef] [Google Scholar]
  18. Chen, T. C., Weng, K. F., Chang, S. C., Lin, J. Y., Huang, P. N. & Shih, S. R.(2008). Development of antiviral agents for enteroviruses. J Antimicrob Chemother 62, 1169–1173.[CrossRef] [Google Scholar]
  19. Chumakov, M., Voroshilova, M., Shindarov, L., Lavrova, I., Gracheva, L., Koroleva, G., Vasilenko, S., Brodvarova, I., Nikolova, M. & other authors(1979). Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60, 329–340.[CrossRef] [Google Scholar]
  20. Colbere-Garapin, F., Christodoulou, C., Crainic, R. & Pelletier, I.(1989). Persistent poliovirus infection of human neuroblastoma cells. Proc Natl Acad Sci U S A 86, 7590–7594.[CrossRef] [Google Scholar]
  21. Collett, M. S., Neyts, J. & Modlin, J. F.(2008). A case for developing antiviral drugs against polio. Antiviral Res 79, 179–187.[CrossRef] [Google Scholar]
  22. Colston, E. & Racaniello, V. R.(1994). Soluble receptor-resistant poliovirus mutants identify surface and internal capsid residues that control interaction with the cell receptor. EMBO J 13, 5855–5862. [Google Scholar]
  23. Colston, E. M. & Racaniello, V. R.(1995). Poliovirus variants selected on mutant receptor-expressing cells identify capsid residues that expand receptor recognition. J Virol 69, 4823–4829. [Google Scholar]
  24. Committee on Development of a Polio Antiviral and Its Potential Role in Global Poliomyelitis Eradication, N. R. C.(2006). Exploring the role of antiviral drugs in the erradication of polio: workshop report. Washington, DC: The National Academies Press.
  25. Crotty, S., Saleh, M. C., Gitlin, L., Beske, O. & Andino, R.(2004). The poliovirus replication machinery can escape inhibition by an antiviral drug that targets a host cell protein. J Virol 78, 3378–3386.[CrossRef] [Google Scholar]
  26. Cuconati, A., Molla, A. & Wimmer, E.(1998). Brefeldin A inhibits cell-free, de novo synthesis of poliovirus. J Virol 72, 6456–6464. [Google Scholar]
  27. De Palma, A. M., Heggermont, W., Lanke, K., Coutard, B., Bergmann, M., Monforte, A. M., Canard, B., De Clercq, E., Chimirri, A. & other authors(2008). The thiazolobenzimidazole TBZE-029 inhibits enterovirus replication by targeting a short region immediately downstream from motif C in the nonstructural protein 2C. J Virol 82, 4720–4730.[CrossRef] [Google Scholar]
  28. De Palma, A. M., Thibaut, H. J., van der Linden, L., Lanke, K., Heggermont, W., Ireland, S., Andrews, R., Arimilli, M., Altel, T. & other authors(2009). Mutations in the non-structural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307. Antimicrob Agents Chemother 53, 1850–1857.[CrossRef] [Google Scholar]
  29. Dierssen, U., Rehren, F., Henke-Gendo, C., Harste, G. & Heim, A.(2008). Rapid routine detection of enterovirus RNA in cerebrospinal fluid by a one-step real-time RT-PCR assay. J Clin Virol 42, 58–64.[CrossRef] [Google Scholar]
  30. Eggers, H. J. & Tamm, I.(1961). Spectrum and characteristics of the virus inhibitory action of 2-(α-hydroxybenzyl)-benzimidazole. J Exp Med 113, 657–682.[CrossRef] [Google Scholar]
  31. Heinz, B. A. & Vance, L. M.(1995). The antiviral compound enviroxime targets the 3A coding region of rhinovirus and poliovirus. J Virol 69, 4189–4197. [Google Scholar]
  32. Huang, L., Yuan, X., Aiken, C. & Chen, C. H.(2004). Bifunctional anti-human immunodeficiency virus type 1 small molecules with two novel mechanisms of action. Antimicrob Agents Chemother 48, 663–665.[CrossRef] [Google Scholar]
  33. Irurzun, A., Perez, L. & Carrasco, L.(1992). Involvement of membrane traffic in the replication of poliovirus genomes: effects of brefeldin A. Virology 191, 166–175.[CrossRef] [Google Scholar]
  34. Maynell, L. A., Kirkegaard, K. & Klymkowsky, M. W.(1992). Inhibition of poliovirus RNA synthesis by brefeldin A. J Virol 66, 1985–1994. [Google Scholar]
  35. McMinn, P. C.(2002). An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 26, 91–107.[CrossRef] [Google Scholar]
  36. Mizuta, K., Abiko, C., Murata, T., Matsuzaki, Y., Itagaki, T., Sanjoh, K., Sakamoto, M., Hongo, S., Murayama, S. & Hayasaka, K.(2005). Frequent importation of enterovirus 71 from surrounding countries into the local community of Yamagata, Japan, between 1998 and 2003. J Clin Microbiol 43, 6171–6175.[CrossRef] [Google Scholar]
  37. Mosser, A. G., Sgro, J. Y. & Rueckert, R. R.(1994). Distribution of drug resistance mutations in type 3 poliovirus identifies three regions involved in uncoating functions. J Virol 68, 8193–8201. [Google Scholar]
  38. Oberste, M. S., Moore, D., Anderson, B., Pallansch, M. A., Pevear, D. C. & Collett, M. S.(2009).In vitro antiviral activity of V-073 against polioviruses. Antimicrob Agents Chemother 53, 4501–4503.[CrossRef] [Google Scholar]
  39. Otto, M. J., Fox, M. P., Fancher, M. J., Kuhrt, M. F., Diana, G. D. & McKinlay, M. A.(1985).In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother 27, 883–886.[CrossRef] [Google Scholar]
  40. Pelletier, I., Duncan, G. & Colbere-Garapin, F.(1998). One amino acid change on the capsid surface of poliovirus Sabin 1 allows the establishment of persistent infections in HEp-2c cell cultures. Virology 241, 1–13.[CrossRef] [Google Scholar]
  41. Rotbart, H. A.(2002). Treatment of picornavirus infections. Antiviral Res 53, 83–98.[CrossRef] [Google Scholar]
  42. Sabin, A. B.(1965). Oral poliovirus vaccine. History of its development and prospects for eradication of poliomyelitis. JAMA 194, 872–876.[CrossRef] [Google Scholar]
  43. Salk, J. E., Bazeley, P. L., Bennett, B. L., Krech, U., Lewis, L. J., Ward, E. N. & Youngner, J. S.(1954). Studies in human subjects on active immunization against poliomyelitis. II. A practical means for inducing and maintaining antibody formation. Am J Public Health Nations Health 44, 994–1009.[CrossRef] [Google Scholar]
  44. Shih, S. R., Tsai, M. C., Tseng, S. N., Won, K. F., Shia, K. S., Li, W. T., Chern, J. H., Chen, G. W., Lee, C. C. & other authors(2004). Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone. Antimicrob Agents Chemother 48, 3523–3529.[CrossRef] [Google Scholar]
  45. Shimizu, H., Agoh, M., Agoh, Y., Yoshida, H., Yoshii, K., Yoneyama, T., Hagiwara, A. & Miyamura, T.(2000). Mutations in the 2C region of poliovirus responsible for altered sensitivity to benzimidazole derivatives. J Virol 74, 4146–4154.[CrossRef] [Google Scholar]
  46. Wang, S. M., Lei, H. Y., Huang, K. J., Wu, J. M., Wang, J. R., Yu, C. K., Su, I. J. & Liu, C. C.(2003). Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 188, 564–570.[CrossRef] [Google Scholar]
  47. Wikel, J. H., Paget, C. J., DeLong, D. C., Nelson, J. D., Wu, C. Y., Paschal, J. W., Dinner, A., Templeton, R. J., Chaney, M. O. & other authors(1980). Synthesis of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine. Inhibitors of rhinovirus multiplication. J Med Chem 23, 368–372.[CrossRef] [Google Scholar]
/content/journal/jgv/10.1099/vir.0.023374-0
Loading
A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection
J. Gen. Virol. 91, 2734 (2010); https://doi.org/10.1099/vir.0.023374-0
/content/journal/jgv/10.1099/vir.0.023374-0
/content/journal/jgv/10.1099/vir.0.023374-0
Loading

Data & Media loading...

Supplements

vol. , part 11, pp. 2734 - 2744

Characterization of G2396A and A2797U mutations identified in the structural protein-coding region of an EV71 mutant resistant to AN-12-H5 [PDF](46 KB)

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error