1887

Abstract

SUMMARY

The new antiviral substance phosphonoformate (PFA) has been tested in a cell-free system for its effect on reverse transcriptases from an avian retrovirus (avian myeloblastosis virus, AMV) and from mammalian retroviruses (Rauscher leukaemia virus, RMuLV; bovine leukaemia virus; baboon endogenous virus; simian sarcoma virus; visna virus). The observed inhibitory effect of PFA has been compared with that of a structurally related substance, phosphonoacetate (PAA). Phosphonoformate, at a concentration of 100 µ, reduced the activities of all the above mentioned polymerases by 90% when (rA).(dT) was used as a template/primer. The dose-response curves for AMV and RMuLV polymerases primed with (rA).(dT) showed PFA to be a 1000-fold more active than PAA; the RMuLV polymerase activity was reduced to 50% after incubation with 0.7 µ-PFA and 0.7 m-PAA, respectively. There was no difference in PFA inhibition of virus-associated and purified reverse transcriptase activity. Results with various synthetic templates showed that both the RNA- and the DNA-dependent polymerase activities of reverse transcriptase were inhibited by PFA. The endogenous polymerase activity of AMV was inhibited to 50% at 100 µ-PFA, while PAA had no effect. The PFA inhibition was dependent on whether Mg or Mn was used as divalent cation in the assay. Phosphonoformate arrested DNA synthesis immediately after being added to the assay system. The mechanism of inhibition of the AMV polymerase was non-competitive with respect to substrate and template and the apparent inhibition constants were 16 µ and 9 µ, respectively.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-45-2-273
1979-11-01
2024-04-26
Loading full text...

Full text loading...

/deliver/fulltext/jgv/45/2/JV0450020273.html?itemId=/content/journal/jgv/10.1099/0022-1317-45-2-273&mimeType=html&fmt=ahah

References

  1. Alenius S., Dinter Z., Öberg B. 1978; Therapeutic effect of trisodium phosphonoformate on cutaneous herpesvirus infection in guinea pigs. Antimicrobial Agents and Chemotherapy 14:408–413
    [Google Scholar]
  2. Allaudeen H. S., Bertino J. R. 1978; Inhibition of activities of DNA polymerases α, β, γ and reverse transcriptase of L 1210 cells by phosphonoacetic acid. Biochimica et Biophysica Acta 520:490–497
    [Google Scholar]
  3. Baltimore D. 1970; RNA–dependent DNA polymerase in virions of RNA tumor viruses. Nature, London1209–1211
    [Google Scholar]
  4. Chandra P., Steel L. K., Ebener U., Woltersdorf M., Laube H., Kornhuber B., Mildner B., Götz A. 1977; Chemical inhibitors of oncoviral DNA polymerases. Biological implications, and their mode of action. Pharmacology and Therapeutics A 1:231–287
    [Google Scholar]
  5. Chirigos M. A., Papas T. S. 1975; Immunological and chemotherapeutic prevention and control of oncogenic viruses. Advances in Pharmacology and Chemotherapy 12:89–124
    [Google Scholar]
  6. Helgstrand E., Eriksson B., Johansson N. G., Lannerö B., Larsson A., Misiorny A., Norën J. O., Sjöberg B., Stenberg K., Stening G., Stridh S., Öberg B., Alenius S., Philipson L. 1978; Trisodium phos-phonoformate, a new antiviral compound. Science 201:819–821
    [Google Scholar]
  7. Leinbach S. S., Reno J. M., Lee L. F., Isbell A. F., Boezi J. A. 1976; Mechanism of phosphonoacetate inhibition of herpesvirus-induced DNA polymerase. Biochemistry 15:426–430
    [Google Scholar]
  8. Van Der Maaten M. J., Miller J. M., Boothe A. D. 1974; Replicating type-C virus particles in monolayer cell cultures of tissue from cattle with lymphosarcoma. Journal of the National Cancer Institute 42:491–498
    [Google Scholar]
  9. Mao J. C.-H., Robishaw E. E. 1975; Mode of inhibition of herpes simplex virus DNA polymerase by phosphonoacetate. Biochemistry 14 (24):5475–5479
    [Google Scholar]
  10. Nordenfelt E., Helgstrand E., Öberg B. 1978; Trisodium phosphonoformate inhibits hepatitis B Dane particle DNA polymerase. IVth International Congress for Virology abstract W 28/5 Centre for Agricultural Publishing and Documentation: Wageningen;
    [Google Scholar]
  11. Nylén P. 1924; Beitrag zur Kenntnis der organischen Phosphorverbindungen. Chemische Berichte 57 B:1023–1038
    [Google Scholar]
  12. Reno J. M., Lee L. E., Boezi J. A. 1978; Inhibition of herpesvirus replication and herpesvirus-induced deoxyribonucleic acid polymerase by phosphonoformate. Antimicrobial Agents and Chemotherapy 13:188–192
    [Google Scholar]
  13. Sabourin C. L. K., Reno J. M., Boezi J. A. 1978; Inhibition of eucaryotic DNA polymerases by phosphonoacetate and phosphonoformate. Archives of Biochemistry and Biophysics 187:96–101
    [Google Scholar]
  14. Shannon W. 1976; Selective inhibitors of RNA tumor virus replication in vitro and evaluation of candidate antiviral agents in vivo. Annals of the New York Academy of Sciences 284:472–502
    [Google Scholar]
  15. Stenberg K., Larsson A. 1978; Reversible effects on cellular metabolism and proliferation by trisodium phosphonoformate. Antimicrobial Agents and Chemotherapy 14:727–730
    [Google Scholar]
  16. Sundquist B., Larner E. 1979; Phosphonoformate inhibition of visna virus replication. Journal of Virology (in the press)
    [Google Scholar]
  17. Temin H., Mizutani S. 1970; RNA–dependent DNA polymerase in virions of Rous sarcoma virus. Nature, London 226:1211–1213
    [Google Scholar]
  18. Vamvakopoulos N. C., Vournakis J. N., Marcus S. L. 1977; The effect of magnesium and manganese ions on the structure and template activity for reverse transcriptase of polyribocytidylate and its 2′-o-methyl derivative. Nucleic Acid Research 4:3589–3597
    [Google Scholar]
  19. Verma I. M. 1977; The reverse transcriptase. Biochimica et Biophysica Acta 473:1–38
    [Google Scholar]
  20. Wehrli W. 1977; Ansamycins, chemistry, biosynthesis and biological activity. Topics in Current Chemistry vol 77 pp 21–49 New York, Vienna: Springer Verlag;
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-45-2-273
Loading
/content/journal/jgv/10.1099/0022-1317-45-2-273
Loading

Data & Media loading...

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