1887

Abstract

HBB [2-(α-hydroxybenzyl)-benzimidazole] and guanidine are potent inhibitors of picornavirus replication. Among other evidence, limited cross-resistance and a synergistic effect of both inhibitors suggest similar but not identical mechanisms of antiviral action. Echovirus-9 variants resistant to each of these drugs were characterized and sequenced. Complete resistance to HBB or guanidine was shown to be due to single but different point mutations in the non-structural protein 2C. Protein 2C was expressed as GST fusion and His-tagged proteins for the wild-type and various mutants. Although three mutations were located in or near conserved NTP binding motifs, NTPase activity was not altered in the presence of HBB or guanidine.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-4-895
2000-04-01
2019-08-22
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/4/0810895a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-4-895&mimeType=html&fmt=ahah

References

  1. Argos, P., Kamer, G., Nicklin, M. J. H. & Wimmer, E. ( 1984; ). Similarity in the gene organization and homology between proteins of animal picornaviruses and a plant comovirus suggest common ancestry of these virus families. Nucleic Acids Research 12, 7251-7267.[CrossRef]
    [Google Scholar]
  2. Ausubel, F. M., Brent, R., Kingston, R. E., Moore, D. D., Seidmann, J. G., Smith, J. A. & Struhl, K. (1994). Current Protocols in Molecular Biology. New York: John Wiley.
  3. Baltera, J. F.Jr & Tershak, D. R. ( 1989; ). Guanidine-resistant mutants of poliovirus have distinct mutations in polypeptide 2C. Journal of Virology 63, 4441-4444.
    [Google Scholar]
  4. 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. Journal of Virology 64, 1156-1163.
    [Google Scholar]
  5. Caliguiri, L. A. & Tamm, I. ( 1973; ). Guanidine and 2-(α-hydroxybenzyl)-benzimidazole (HBB): selective inhibitors of picornavirus multiplication. In Selective Inhibitors of Viral Function, pp. 257-293. Edited by W. A. Carter. Florida: CRC Press.
  6. Cuconati, A., Xiang, W., Lahser, F., Pfister, T. & Wimmer, E. ( 1998; ). A protein linkage map of the P2-nonstructural proteins of poliovirus. Journal of Virology 72, 1297-1307.
    [Google Scholar]
  7. Echeverri, A. C. & Dasgupta, A. ( 1995; ). Amino terminal regions of poliovirus 2C protein mediate membrane binding. Virology 208, 540-553.[CrossRef]
    [Google Scholar]
  8. Eggers, H. J. ( 1977; ). Selective inhibition of uncoating of echovirus 12 by rhodanine. Virology 78, 241-252.[CrossRef]
    [Google Scholar]
  9. Eggers, H. J. ( 1982; ). Benzimidazoles. Selective inhibitors of picornavirus replication in cell culture and in the organism. In Chemotherapy of Viral Infections, pp. 377-417. Edited by P. E. Came & L. A. Caliguiri. Berlin, Heidelberg, New York: Springer Verlag.
  10. Eggers, H. J. & Sabin, A. B. ( 1959; ). Factors determining pathogenicity of variants of ECHO 9 virus for newborn mice. Journal of Experimental Medicine 110, 951-967.[CrossRef]
    [Google Scholar]
  11. Eggers, H. J. & Tamm, I. ( 1961; ). Spectrum and characteristics of the virus inhibitory action of 2-(α-hydroxybenzyl)-benzimidazole. Journal of Experimental Medicine 113, 657-682.[CrossRef]
    [Google Scholar]
  12. Eggers, H. J. & Tamm, I. ( 1963a; ). Inhibition of enterovirus ribonucleic acid synthesis by 2-(α-hydroxybenzyl)-benzimidazole. Nature 197, 1327-1328.[CrossRef]
    [Google Scholar]
  13. Eggers, H. J. & Tamm, I. ( 1963b; ). Synergistic effect of 2-(α-hydroxybenzyl)-benzimidazole and guanidine on picornavirus reproduction. Nature 199, 513-514.
    [Google Scholar]
  14. Gorbalenya, A. E., Koonin, E. V. & Wolf, Y. I. ( 1990; ). A new superfamily of putative NTP-binding domains encoded by genomes of small DNA and RNA viruses. FEBS Letters 262, 145-148.[CrossRef]
    [Google Scholar]
  15. Hadaschik, D., Klein, M., Zimmermann, H., Eggers, H. J. & Nelsen-Salz, B. ( 1999; ). Dependence of echovirus 9 on the enteroviral replication inhibitor 2-(α-hydroxybenzyl)-benzimidazole (HBB) maps to the nonstructural protein 2C. Journal of Virology 73, 10536-10539.
    [Google Scholar]
  16. Kadaré, G. & Haenni, A. L. ( 1997; ). Virus-encoded RNA helicases. Journal of Virology 71, 2583-2590.
    [Google Scholar]
  17. Klein, M., Eggers, H. J. & Nelsen-Salz, B. ( 1999; ). Echovirus 9 strain Barty nonstructural protein 2C has NTPase activity. Virus Research 65, 155-160.[CrossRef]
    [Google Scholar]
  18. Li, J. P. & Baltimore, D. ( 1990; ). An intragenic revertant of a poliovirus 2C mutant has an uncoating defect. Journal of Virology 64, 1102-1107.
    [Google Scholar]
  19. Mirzayan, C. & Wimmer, E. ( 1994; ). Biochemical studies on poliovirus polypeptide 2C: evidence for ATPase activity. Virology 199, 176-187.[CrossRef]
    [Google Scholar]
  20. Pfister, T. & Wimmer, E. ( 1999; ). Characterization of the nucleoside triphosphatase activity of poliovirus protein 2C reveals a mechanism by which guanidine inhibits poliovirus replication. Journal of Biological Chemistry 274, 6992-7001.[CrossRef]
    [Google Scholar]
  21. Pincus, S. E. & Wimmer, E. ( 1986; ). Production of guanidine-resistant and -dependent poliovirus mutants from cloned cDNA: mutations in polypeptide 2C are directly responsible for altered guanidine sensitivity. Journal of Virology 60, 793-796.
    [Google Scholar]
  22. Pincus, S. E., Diamond, D. C., Emini, E. A. & Wimmer, E. ( 1986; ). Guanidine-selected mutants of poliovirus: mapping of point mutations to polypeptide 2C. Journal of Virology 57, 638-646.
    [Google Scholar]
  23. Rodriguez, P. L. & Carrasco, L. ( 1993; ). Poliovirus protein 2C has ATPase and GTPase activities. Journal of Biological Chemistry 268, 8105-8110.
    [Google Scholar]
  24. Rodriguez, P. L. & Carrasco, L. ( 1995; ). Poliovirus protein 2C contains two regions involved in RNA binding activity. Journal of Biological Chemistry 270, 10105-10112.[CrossRef]
    [Google Scholar]
  25. Rueckert, R. ( 1996; ). Picornaviridae: the viruses and their replication. In Virology, pp. 609-654. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. New York: Raven Press.
  26. Tolskaya, E. A., Romanova, L. I., Kolesnikova, M. S., Gmyl, A. P., Gorbalenya, A. P. & Agol, V. I. ( 1994; ). Genetic studies on the poliovirus 2C protein, an NTPase. A plausible mechanism of guanidine effect on the 2C function and evidence for the importance of 2C oligomerisation. Journal of Molecular Biology 236, 1310-1323.[CrossRef]
    [Google Scholar]
  27. Vance, L. M., Moscufo, N., Chow, M. & Heinz, B. A. ( 1997; ). Poliovirus 2C region functions during encapsidation of viral RNA. Journal of Virology 71, 8759-8765.
    [Google Scholar]
  28. Wimmer, E., Hellen, C. U. T. & Cao, X. ( 1993; ). Genetics of poliovirus. Annual Reviews in Genetics 27, 353-436.[CrossRef]
    [Google Scholar]
  29. Zimmermann, H., Eggers, H. J. & Nelsen-Salz, B. ( 1996; ). Molecular cloning and sequence determination of the complete genome of the virulent echovirus 9 strain Barty. Virus Genes 12, 149-154.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-81-4-895
Loading
/content/journal/jgv/10.1099/0022-1317-81-4-895
Loading

Data & Media loading...

Most Cited This Month

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