Archives of Virology

, Volume 106, Issue 1–2, pp 51–61 | Cite as

Lack of quantitative correlation between inhibition of replication of rhinoviruses by an antiviral drug and their stabilization

  • K. Andries
  • B. Dewindt
  • J. Snoeks
  • R. Willebrords
Original Papers

Summary

R 61 837, a new antirhinovirus compound, was able to protect several susceptible rhinoviruses against inactivation by mild acidification or heat. This observation strengthens the hypothesis that the drug exerts antiviral activity by a direct interaction with the viral protein capsid to stabilize the particle. However, the minimal concentrations necessary to inhibit either acetate or citrate or heat inactivation were different for each of five tested serotypes and we therefore conclude that stabilization and inhibition of replication are not causally linked but parallel events, both independently resulting from the binding of the drug to the viral capsid.

Studies using drug resistant mutants of HRV 51 and HRV 9 confirmed this lack of quantitative correlation. The mutants were also shown to be cross resistant to a panel of seven different reference antirhinoviral drugs including SDS, WIN 51711, chalcone, dichloroflavan and MDL 20,610. This indicates that all these compounds bind to the same site corresponding to the hydrophobic pocket within the viral protein VP 1 β-barrel structure of HRV 14.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ahmad ALM, Dowsett AB, Tyrrell DAJ (1987) Studies of rhinovirus resistant to an antiviral chalcone. Antiviral Res 8: 27–39Google Scholar
  2. 2.
    Andries K, Dewindt B, De Brabander M, Stokbroekx R, Janssen PAJ (1988) In vitro activity of R 61 837, a new antirhinovirus compound. Arch Virol 101: 155–167Google Scholar
  3. 3.
    Ash RJ, Parker RA, Hagan AC, Mayer GD (1979) RMI 15,731 (1-[5-tetradecycloxy-2-furanyl]-ethanone), a new antirhinovirus compound. Antimicrob Agents Chemother 16: 301–305Google Scholar
  4. 4.
    Bauer DJ, Selway JWT, Batchelor JF, Tisdale M, Caldwell IC, Young DAB (1981) 4′,6-dichloroflavan (BW 683 C), a new anti-rhinovirus compound. Nature 292: 369–370Google Scholar
  5. 5.
    Badger J, Minor I, Kremer M, Oliveira MA, Smith TJ, Griffith JP, Guerin DM, Krishnaswamy S, Luo M, Rossmann MG, McKinlay MA, Diana GD, Dutko FJ, Fancher M, Reuckert RR, Heinz BA (1988) Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc Natl Acad Sci USA 85: 3304–3308Google Scholar
  6. 6.
    Caliguiri LA, McSharry JJ, Lawrence GW (1980) Effect of arildone on modifications of poliovirus in vitro. Virology 105: 86–93Google Scholar
  7. 7.
    Delong DC, Nelson JD, Wu CYE, Warren B, Wikel J, Chamberlin J, Montgomery D, Paget CJ (1978) Virus inhibition studies with AR-336. I: tissue culture activity. In: Abstracts of annual meeting of American Society for Microbiology, Washington, DC, p 234Google Scholar
  8. 8.
    Eggers HJ, Rosenwirth B (1988) Isolation and characterization of an arildone-resistant poliovirus 2 mutant with an altered capsid protein VP 1. Antiviral Res 9: 23–26Google Scholar
  9. 9.
    Fox MP, Otto MJ, McKinlay MA (1986) Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug. Antimicrob Agents Chemother 30: 110–116Google Scholar
  10. 10.
    Ishitsuka H, Ninomya YN, Ohsawa C, Fujiu M, Suhura Y (1982) Direct and specific inactivation of rhinovirus by chalcone Ro 09-410. Antimicrob Agents Chemother 22: 617–621Google Scholar
  11. 11.
    Ishitsuka H, Ninomya YN, Suhura Y (1986) Molecular basis of drug resistance to new antiviral agents. J Antimicrob Chemother 18 [Suppl B]: 11–18Google Scholar
  12. 12.
    Kenny MT, Dulworth JK, Torney HL (1985) In vitro and in vivo antipicornavirus activity of some phenoxy pyridinecarbonitriles. Antimicrob Agents Chemother 28: 745–75013Google Scholar
  13. 13.
    Kenny MT, Dulworth JK, Bargar TM, Torney HL, Graham MC, Manelli AM (1986) In vitro antiviral activity of the 6-substituted 2-(3′,4′-dichlorophenoxy)-2H-pyrano[2,3-b]pyridines MDL 20,610, MDL 20,646, and MDL 20,957. Antimicrob Agents Chemother 30: 516–518Google Scholar
  14. 14.
    Kenny MT, Torney HL, Dulworth JK (1988) Mechanism of action of the antiviral compound MDL 20,610. Antiviral Res 9: 249–261Google Scholar
  15. 15.
    Kuhrt MF, Fancher MJ, McKinlay MA, Lennert SD (1984) Virucidal activity of glutaric acid and evidence for dual mechanism of action. Antimicrob Agents Chemother 26: 924–927Google Scholar
  16. 16.
    Madshus IG, Olsnes S, Sandvig K (1984) Different pH requirements for entry of two picornaviruses, human rhinovirus 2 and murine encephalomyocarditis virus. Virology 139: 346–357Google Scholar
  17. 17.
    Lonberg-Holm K, Noble-Harvey J (1973) Comparison of in vitro and cell-mediated alteration of a human rhinovirus and its inhibition by sodium dodecyl sulfate. J Virol 12: 819–826Google Scholar
  18. 18.
    Lonberg-Holm K, Gosser LB, Kauer LC (1975) Early alteration of poliovirus in infected cells and its specific inhibition. J Gen Virol 27: 329–342Google Scholar
  19. 19.
    Ninomya Y, Ohsawa C, Aoyama M, Umeda I, Suhara Y, Ishitsuka H (1984) Antivirus agent, Ro 09-410, binds to rhinovirus specifically and stabilizes the virus conformation. Virology 134: 269–276Google Scholar
  20. 20.
    Ninomya Y, Aoyama M, Umeda I, Suhara Y, Ishitsuka H (1985) Comparative studies on the modes of action of the antirhinovirus agents Ro 09-410, Ro 09-0179, RMI-15,731, 4′,6-dichloroflavan, and enviroxime. Antimicrob Agents Chemother 27: 595–599Google Scholar
  21. 21.
    Otto MJ, Fox MP, Fancher MJ, Kuhrt MF, Diana GD, McKinlay MA (1985) In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother 27: 883–886Google Scholar
  22. 22.
    Rosenwirth B, Eggers HJ (1979) Early processes of echovirus 12-infection: elution, penetration and uncoating under the influence of rhodanine. Virology 97: 241–255Google Scholar
  23. 23.
    Schrom M, Laffin JA, Evans B, McSharry JJ, Caliguiri LA (1982) Isolation of poliovirus variants resistant and dependent on arildone. Virology 122: 492–497Google Scholar
  24. 24.
    Smith TJ, Kremer MJ, Lou M, Vriend G, Arnold E, Kamer G, Rossmann MG, McKinlay MA, Diana GD, Otto MJ (1986) The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Science 233: 1286–1293Google Scholar
  25. 25.
    Tisdale M, Selway JWT (1984) Effect of dichloroflavan (BW 683 C) on the stability and uncoating of rhinovirus type 1 B. J Antimicrob Chemother 14 [Suppl 1]: 97–105Google Scholar
  26. 26.
    Torney HL, Dulworth JK, Steward DL (1982) Antiviral activity and mechanism of action of 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL 860). Antimicrob Agents Chemother 22: 635–638Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • K. Andries
    • 1
  • B. Dewindt
    • 1
  • J. Snoeks
    • 1
  • R. Willebrords
    • 1
  1. 1.Department of VirologyJanssen Research FoundationBeerseBelgium

Personalised recommendations