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. 1987 Jan;31(1):76–80. doi: 10.1128/aac.31.1.76

Inhibiting effect of (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine on varicella-zoster virus replication in cell culture.

G Abele, A Karlström, J Harmenberg, S Shigeta, A Larsson, B Lindborg, B Wahren
PMCID: PMC174655  PMID: 3032092

Abstract

The activity and mode of action of the new nucleoside analog (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (2HM-HBG) against varicella-zoster virus (VZV) were determined. In cell culture, replication of different strains of VZV was inhibited to 50% by 0.4 to 0.7 microM 2HM-HBG, while 685 microM was required to inhibit 50% of the DNA synthesis in uninfected human lung fibroblasts. A thymidine kinase-negative VZV strain was not inhibited by 100 microM 2HM-HBG. Inhibition of VZV replication was not reversible after 7 to 14 days of incubation, depending on the multiplicity of VZV. 2HM-HBG was shown to be selectively phosphorylated by purified VZV thymidine kinase, with an inhibition constant of 32.5 microM. The antiviral activity of 2HM-HBG in cell culture was decreased by the addition of deoxythymidine and deoxycytidine but not by other ribo- or deoxyribonucleosides.

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Selected References

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

  1. Cheng Y. C., Tsou T. Y., Hackstadt T., Mallavia L. P. Induction of thymidine kinase and DNase in varicella-zoster virus-infected cells and kinetic properties of the virus-induced thymidine kinase. J Virol. 1979 Jul;31(1):172–177. doi: 10.1128/jvi.31.1.172-177.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Dobersen M. J., Greer S. An assay for pyrimidine deoxyribonucleoside kinase using gamma-32P-labeled ATP. Anal Biochem. 1975 Aug;67(2):602–610. doi: 10.1016/0003-2697(75)90335-8. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Hackstadt T., Mallavia L. P. Deoxypyrimidine nucleoside metabolism in varicella-zoster virus-infected cells. J Virol. 1978 Feb;25(2):510–517. doi: 10.1128/jvi.25.2.510-517.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Harmenberg J. Interactions between virus and antiviral compounds in the host cell. Med Biol. 1984;62(6):299–303. [PubMed] [Google Scholar]
  6. Harmenberg J. Intracellular pools of thymidine reduce the antiviral action of acyclovir. Intervirology. 1983;20(1):48–51. doi: 10.1159/000149373. [DOI] [PubMed] [Google Scholar]
  7. Harmenberg J., Wahren B. Influence of cell culture conditions on the inhibition of herpes simplex virus type 1 replication by acyclovir. Intervirology. 1982;17(4):215–221. doi: 10.1159/000149291. [DOI] [PubMed] [Google Scholar]
  8. Harmenberg J., Wahren B., Oberg B. Influence of cells and virus multiplicity on the inhibition of herpesviruses with acycloguanosine. Intervirology. 1980;14(5-6):239–244. doi: 10.1159/000149192. [DOI] [PubMed] [Google Scholar]
  9. Helgstrand E., Eriksson B., Johansson N. G., Lannerö B., Larsson A., Misiorny A., Norén J. O., Sjöberg B., Stenberg K., Stening G. Trisodium phosphonoformate, a new antiviral compound. Science. 1978 Sep 1;201(4358):819–821. doi: 10.1126/science.210500. [DOI] [PubMed] [Google Scholar]
  10. Karlström A. R., Källander C. F., Abele G., Larsson A. Acyclic guanosine analogs as substrates for varicella-zoster virus thymidine kinase. Antimicrob Agents Chemother. 1986 Jan;29(1):171–174. doi: 10.1128/aac.29.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kit S., Leung W. C., Trkula D., Jorgensen G. Gel electrophoresis and isoelectric focusing of mitochondrial and viral-induced thymidine kinases. Int J Cancer. 1974 Feb 15;13(2):203–218. doi: 10.1002/ijc.2910130208. [DOI] [PubMed] [Google Scholar]
  12. Kit S., Leung W. C., Trkula D. Properties of mitochondrial thymidine kinases of parental and enzyme-deficient HeLa cells. Arch Biochem Biophys. 1973 Oct;158(2):503–513. doi: 10.1016/0003-9861(73)90542-0. [DOI] [PubMed] [Google Scholar]
  13. Källander C. F., Gronowitz J. S., Olding-Stenkvist E. Rapid diagnosis of varicella-zoster virus infection by detection of viral deoxythymidine kinase in serum and vesicle fluid. J Clin Microbiol. 1983 Feb;17(2):280–287. doi: 10.1128/jcm.17.2.280-287.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lee L. S., Cheng Y. C. Human deoxythymidine kinase. I. Purification and general properties of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia. J Biol Chem. 1976 May 10;251(9):2600–2604. [PubMed] [Google Scholar]
  15. Schnürer J., Oberg B. Inhibitory effects of foscarnet on herpesvirus multiplication in cell culture. Arch Virol. 1981;68(3-4):203–209. doi: 10.1007/BF01314573. [DOI] [PubMed] [Google Scholar]
  16. Shepp D. H., Dandliker P. S., Meyers J. D. Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine. N Engl J Med. 1986 Jan 23;314(4):208–212. doi: 10.1056/NEJM198601233140404. [DOI] [PubMed] [Google Scholar]
  17. Sundqvist V. A., Wahren B. Development of sensitive and enzyme-linked immunoassays for herpesvirus antigens and some applications. Dev Biol Stand. 1982;52:245–253. [PubMed] [Google Scholar]
  18. Wahren B., Oberg B. Reversible inhibition of cytomegalovirus replication by phosphonoformate. Intervirology. 1980;14(1):7–15. doi: 10.1159/000149156. [DOI] [PubMed] [Google Scholar]
  19. Wahren B., Wahren P., Harmenberg J., Sundqvist V. A. Computer-based virus sensitivity assay and neutralization method. Applications for herpesviruses. J Virol Methods. 1983 May;6(5):271–282. doi: 10.1016/0166-0934(83)90042-3. [DOI] [PubMed] [Google Scholar]
  20. Yokota T., Ogata M., Shigeta S. A mutant strain of varicella-zoster virus deficient in thymidine kinase-inducing activity. Fukushima J Med Sci. 1983 Jul;29(3-4):101–111. [PubMed] [Google Scholar]

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