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. 1990 Oct;34(10):1986–1990. doi: 10.1128/aac.34.10.1986

Potent inhibition of hepatitis B virus production in vitro by modified pyrimidine nucleosides.

E Matthes 1, P Langen 1, M von Janta-Lipinski 1, H Will 1, H C Schröder 1, H Merz 1, B E Weiler 1, W E Müller 1
PMCID: PMC171976  PMID: 2291664

Abstract

2',3'-Dideoxy-3'-fluorothymidine (FddThd), 2',3'-didehydro-2',3'- dideoxythymidine (ddeThd), and 3'-fluoro-5-methyl-deoxycytidine (FddMeCyt) are, in their triphosphate forms, selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase. We report that 0.3 microM FddThd, FddMeCyt, or ddeThd as well as 3'-chloro-5-methyl-deoxycytidine (ClddMeCyt) or 3'-amino-5-methyl-deoxycytidine (AddMeCyt) almost completely blocked production of hepatitis B virus (HBV) particles by HBV DNA-transfected cell line 2.2.15 in vitro. Only at an at least 10-fold-higher concentration was a cytotoxic effect observed. These results indicate that FddThd, FddMeCyt, ClddMeCyt, AddMeCyt, and ddeThd are potent anti-HBV agents in vitro.

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1986

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Selected References

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  1. Bollum F. J. Mammalian DNA polymerases. Prog Nucleic Acid Res Mol Biol. 1975;15(0):109–144. doi: 10.1016/s0079-6603(08)60118-x. [DOI] [PubMed] [Google Scholar]
  2. De Clercq E. Suramin: a potent inhibitor of the reverse transcriptase of RNA tumor viruses. Cancer Lett. 1979 Nov;8(1):9–22. doi: 10.1016/0304-3835(79)90017-x. [DOI] [PubMed] [Google Scholar]
  3. Gerber M. A., Thung S. N. Molecular and cellular pathology of hepatitis B. Lab Invest. 1985 Jun;52(6):572–590. [PubMed] [Google Scholar]
  4. Hirt B. Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol. 1967 Jun 14;26(2):365–369. doi: 10.1016/0022-2836(67)90307-5. [DOI] [PubMed] [Google Scholar]
  5. Horwitz J. R., Chua J., Da Rooge M. A., Noel M., Klundt I. L. Nucleosides. IX. The formation of 2',2'-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction. J Org Chem. 1966 Jan;31(1):205–211. doi: 10.1021/jo01339a045. [DOI] [PubMed] [Google Scholar]
  6. Jochum C., Voth R., Rossol S., Meyer zum Büschenfelde K. H., Hess G., Will H., Schröder H. C., Steffen R., Müller W. E. Immunosuppressive function of hepatitis B antigens in vitro: role of endoribonuclease V as one potential trans inactivator for cytokines in macrophages and human hepatoma cells. J Virol. 1990 May;64(5):1956–1963. doi: 10.1128/jvi.64.5.1956-1963.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kakumu S., Tahara H., Fuji A., Yoshioka K. Interleukin 1 alpha production by peripheral blood monocytes from patients with chronic liver disease and effect of sera on interleukin 1 alpha production. J Clin Lab Immunol. 1988 Jul;26(3):113–119. [PubMed] [Google Scholar]
  8. Langen P., Kowollik G., Etzold G., Venner H., Reinert H. The phosphorylation of 3'-deoxy-3'-fluorothymidine and its incorporation into DNA in a cellfree system from tumor cells. Acta Biol Med Ger. 1972;29(4):483–494. [PubMed] [Google Scholar]
  9. Marier R. The reporting of communicable diseases. Am J Epidemiol. 1977 Jun;105(6):587–590. doi: 10.1093/oxfordjournals.aje.a112424. [DOI] [PubMed] [Google Scholar]
  10. Matthes E., Lehmann C., Scholz D., Rosenthal H. A., Langen P. Phosphorylation, anti-HIV activity and cytotoxicity of 3'-fluorothymidine. Biochem Biophys Res Commun. 1988 Jun 16;153(2):825–831. doi: 10.1016/s0006-291x(88)81170-7. [DOI] [PubMed] [Google Scholar]
  11. Matthes E., Lehmann C., Scholz D., von Janta-Lipinski M., Gaertner K., Rosenthal H. A., Langen P. Inhibition of HIV-associated reverse transcriptase by sugar-modified derivatives of thymidine 5'-triphosphate in comparison to cellular DNA polymerases alpha and beta. Biochem Biophys Res Commun. 1987 Oct 14;148(1):78–85. doi: 10.1016/0006-291x(87)91078-3. [DOI] [PubMed] [Google Scholar]
  12. Meisel H., Reimer K., von Janta-Lipinski M., Bärwolff D., Matthes E. Inhibition of hepatitis B virus DNA polymerase by 3'-fluorothymidine triphosphate and other modified nucleoside triphosphate analogs. J Med Virol. 1990 Feb;30(2):137–141. doi: 10.1002/jmv.1890300211. [DOI] [PubMed] [Google Scholar]
  13. Miller R. H., Robinson W. S. Common evolutionary origin of hepatitis B virus and retroviruses. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2531–2535. doi: 10.1073/pnas.83.8.2531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Munro H. N., Fleck A. Recent developments in the measurement of nucleic acids in biological materials. A supplementary review. Analyst. 1966 Feb;91(79):78–88. doi: 10.1039/an9669100078. [DOI] [PubMed] [Google Scholar]
  15. Müller W. E., Geisert M., Zahn R. K., Maidhof A., Bachmann M., Umezawa H. Potentiation of the cytostatic effect of bleomycin on L5178y mouse lymphoma cells by pepleomycin. Eur J Cancer Clin Oncol. 1983 May;19(5):665–670. doi: 10.1016/0277-5379(83)90183-9. [DOI] [PubMed] [Google Scholar]
  16. Müller W. E., Yamazaki Z. I., Sögtrop H. H., Zahn R. K. Action of 1- -D-arabinofuranosylcytosine on mammalian tumor cells. 2. Inhibition of mammalian and oncogenic viral polymerases. Eur J Cancer. 1972 Aug;8(4):421–428. doi: 10.1016/0014-2964(72)90127-2. [DOI] [PubMed] [Google Scholar]
  17. Müller W. E., Zahn R. K., Bittlingmaier K., Falke D. Inhibition of herpesvirus DNA synthesis by 9-beta-D-arabinofuranosyladenine in cellular and cell-free systems. Ann N Y Acad Sci. 1977 Mar 4;284:34–48. doi: 10.1111/j.1749-6632.1977.tb21935.x. [DOI] [PubMed] [Google Scholar]
  18. Offensperger W. B., Walter E., Offensperger S., Zeschnigk C., Blum H. E., Gerok W. Duck hepatitis B virus: DNA polymerase and reverse transcriptase activities of replicative complexes isolated from liver and their inhibition in vitro. Virology. 1988 May;164(1):48–54. doi: 10.1016/0042-6822(88)90618-6. [DOI] [PubMed] [Google Scholar]
  19. Pollard R. B., Smith J. L., Neal A., Gregory P. B., Merigan T. C., Robinson W. S. Effect of vidarabine on chronic hepatitis B virus infection. JAMA. 1978 Apr 21;239(16):1648–1650. [PubMed] [Google Scholar]
  20. Pugh J. C., Weber C., Houston H., Murray K. Expression of the X gene of hepatitis B virus. J Med Virol. 1986 Nov;20(3):229–246. doi: 10.1002/jmv.1890200305. [DOI] [PubMed] [Google Scholar]
  21. Reed K. C., Mann D. A. Rapid transfer of DNA from agarose gels to nylon membranes. Nucleic Acids Res. 1985 Oct 25;13(20):7207–7221. doi: 10.1093/nar/13.20.7207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  23. Sarin P. S., Taguchi Y., Sun D., Thornton A., Gallo R. C., Oberg B. Inhibition of HTLV-III/LAV replication by foscarnet. Biochem Pharmacol. 1985 Nov 15;34(22):4075–4079. doi: 10.1016/0006-2952(85)90392-2. [DOI] [PubMed] [Google Scholar]
  24. Sells M. A., Chen M. L., Acs G. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1005–1009. doi: 10.1073/pnas.84.4.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sprengel R., Kuhn C., Manso C., Will H. Cloned duck hepatitis B virus DNA is infectious in Pekin ducks. J Virol. 1984 Dec;52(3):932–937. doi: 10.1128/jvi.52.3.932-937.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Suzuki S., Lee B., Luo W., Tovell D., Robins M. J., Tyrrell D. L. Inhibition of duck hepatitis B virus replication by purine 2',3'-dideoxynucleosides. Biochem Biophys Res Commun. 1988 Nov 15;156(3):1144–1151. doi: 10.1016/s0006-291x(88)80752-6. [DOI] [PubMed] [Google Scholar]
  27. Will H., Reiser W., Weimer T., Pfaff E., Büscher M., Sprengel R., Cattaneo R., Schaller H. Replication strategy of human hepatitis B virus. J Virol. 1987 Mar;61(3):904–911. doi: 10.1128/jvi.61.3.904-911.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yamashita Y., Koike K., Takaoki M., Matsuda S. Suppression of HBsAg production in PLC/PRF/5 human hepatoma cell line by interferons. Microbiol Immunol. 1988;32(11):1119–1126. doi: 10.1111/j.1348-0421.1988.tb01476.x. [DOI] [PubMed] [Google Scholar]
  29. von Janta-Lipinski M., Langen P. Synthesis of 6-substituted thymine nucleosides. Nucleic Acids Symp Ser. 1981;(9):41–44. [PubMed] [Google Scholar]

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