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
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- 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]
- 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]
- 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]
- 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]
- Harmenberg J. Interactions between virus and antiviral compounds in the host cell. Med Biol. 1984;62(6):299–303. [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]