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. 1980 Nov;18(5):741–745. doi: 10.1128/aac.18.5.741

Inhibition of cellular alpha and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir.

M H St Clair, P A Furman, C M Lubbers, G B Elion
PMCID: PMC284085  PMID: 7192534

Abstract

The effect of the triphosphate of 9-(2-hydroxyethoxymethyl)guanine (acyclovir, acycloguanosine) on cellular alpha deoxyribonucleic acid (DNA) polymerases (DNA nucleotidyltransferases), DNA polymerases of several members of the herpes group, vaccinia virus DNA polymerase, and Friend leukemia virus ribonucleic acid-dependent DNA polymerase was examined. Several viruses, which were found to be susceptible to acyclovir, were found to induce DNA polymerases which were sensitive to acyclovir triphosphate (acyclo-GTP). Human cytomegalovirus and the H29R strain of herpes simplex virus type 1, however, were found to be relatively insusceptible to acyclovir, even though their induced DNA polymerases were inhibited by low concentrations of acyclo-GTP. The amount of acyclovir anabolized to acyclo-GTP was significantly lower for human cytomegalovirus and H29R than for the more susceptible viruses. Vaccinia virus and Friend leukemia virus induced DNA polymerases which were insensitive to inhibition by low concentrations of acyclo-GTP, anabolized little acyclovir to acyclo-GTP, and were found to be insensitive to inhibition by acyclovir. Uninfected WI-38 cells were not susceptible to inhibition by acyclovir, anabolized little acyclovir to acyclo-GTP, and had an alpha DNA polymerase which was insensitive to inhibition by low concentrations of acyclo-GTP.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altman S., Lerman L. S. Kinetics and intermediates in the intracellular synthesis of bacteriophage T4 deoxyribonucleic acid. J Mol Biol. 1970 Jun 14;50(2):235–261. doi: 10.1016/0022-2836(70)90190-7. [DOI] [PubMed] [Google Scholar]
  2. Bassin R. H., Tuttle N., Fischinger P. J. Rapid cell culture assay technic for murine leukaemia viruses. Nature. 1971 Feb 19;229(5286):564–566. doi: 10.1038/229564b0. [DOI] [PubMed] [Google Scholar]
  3. Battula N., Loeb L. A. On the fidelity of DNA replication. Lack of exodeoxyribonuclease activity and error-correcting function in avian myeloblastosis virus DNA polymerase. J Biol Chem. 1976 Feb 25;251(4):982–986. [PubMed] [Google Scholar]
  4. Berns K. I., Silverman C., Weissbach A. Separation of a new deoxyribonucleic acid polymerase from vaccinia-infected HeLa cells. J Virol. 1969 Jul;4(1):15–23. doi: 10.1128/jvi.4.1.15-23.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  6. Collins P., Bauer D. J. Comparison of activity of herpes virus inhibitors. J Antimicrob Chemother. 1977 Mar;3 (Suppl A):73–81. doi: 10.1093/jac/3.suppl_a.73. [DOI] [PubMed] [Google Scholar]
  7. Collins P., Bauer D. J. Relative potencies of anti-herpes compounds. Ann N Y Acad Sci. 1977 Mar 4;284:49–59. doi: 10.1111/j.1749-6632.1977.tb21936.x. [DOI] [PubMed] [Google Scholar]
  8. Elion G. B., Furman P. A., Fyfe J. A., de Miranda P., Beauchamp L., Schaeffer H. J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5716–5720. doi: 10.1073/pnas.74.12.5716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Estes J. E., Huang E. S. Stimulation of cellular thymidine kinases by human cytomegalovirus. J Virol. 1977 Oct;24(1):13–21. doi: 10.1128/jvi.24.1.13-21.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Furman P. A., McGuirt P. V., Keller P. M., Fyfe J. A., Elion G. B. Inhibition by acyclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information. Virology. 1980 Apr 30;102(2):420–430. doi: 10.1016/0042-6822(80)90109-9. [DOI] [PubMed] [Google Scholar]
  11. Furman P. A., St Clair M. H., Fyfe J. A., Rideout J. L., Keller P. M., Elion G. B. Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate. J Virol. 1979 Oct;32(1):72–77. doi: 10.1128/jvi.32.1.72-77.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fyfe J. A., Keller P. M., Furman P. A., Miller R. L., Elion G. B. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J Biol Chem. 1978 Dec 25;253(24):8721–8727. [PubMed] [Google Scholar]
  13. Huang E. S. Human cytomegalovirus. III. Virus-induced DNA polymerase. J Virol. 1975 Aug;16(2):298–310. doi: 10.1128/jvi.16.2.298-310.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hurwitz J., Leis J. P. RNA-dependent DNA polymerase activity of RNA tumor viruses. I. Directing influence of DNA in the reaction. J Virol. 1972 Jan;9(1):116–129. doi: 10.1128/jvi.9.1.116-129.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kit S., Dubbs D. R. Enzyme induction by viruses. Monogr Virol. 1969;2:1–114. [PubMed] [Google Scholar]
  16. Kit S., Jorgensen G. N., Liav A., Zaslavsky V. Purification of vaccinia virus-induced thymidine kinase activity from [35S]methionine-labeled cells. Virology. 1977 Apr;77(2):661–676. doi: 10.1016/0042-6822(77)90490-1. [DOI] [PubMed] [Google Scholar]
  17. Nevins J. R., Joklik W. K. Poly (A) sequences of vaccinia virus messenger RNA: nature, mode of addition and function during translation in vitra and in vivo. Virology. 1975 Jan;63(1):1–14. doi: 10.1016/0042-6822(75)90365-7. [DOI] [PubMed] [Google Scholar]
  18. Nishiyama Y., Rapp F. Anticellular effects of 9-(2-hydroxyethoxymethyl) guanine against herpes simplex virus-transformed cells. J Gen Virol. 1979 Oct;45(1):227–230. doi: 10.1099/0022-1317-45-1-227. [DOI] [PubMed] [Google Scholar]
  19. Schaeffer H. J., Beauchamp L., de Miranda P., Elion G. B., Bauer D. J., Collins P. 9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature. 1978 Apr 13;272(5654):583–585. doi: 10.1038/272583a0. [DOI] [PubMed] [Google Scholar]
  20. Seifert E., Claviez M., Frank H., Hunsmann G., Schwarz H., Schäfer W. XII. Produktion grösserer Mengen von Friend-Virus durch eine permanente Zell-Suspensions-Kultur (Eveline-Suspensions-Zellen) Z Naturforsch C. 1975 Sep-Oct;30(5):698–700. [PubMed] [Google Scholar]
  21. Weissbach A., Hong S. C., Aucker J., Muller R. Characterization of herpes simplex virus-induced deoxyribonucleic acid polymerase. J Biol Chem. 1973 Sep 25;248(18):6270–6277. [PubMed] [Google Scholar]

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