1887

Abstract

SUMMARY

Arildone (WIN 38020), a broad spectrum antiviral, aryl-β-diketone (4-[6-(2-chloro-4-methoxy)phenoxyl]hexyl-3,5-heptanedione), blocks the replication of human cytomegalovirus at a stage prior to the synthesis of virus-specific DNA. Inhibitory action was demonstrated against a number of virus isolates from neonates and immune-compromised patients. Intranuclear sites of virus replication, highlighted by DNA-staining methods or immunofluorescence, were absent after Arildone treatment and corresponded with the lack of ultrastructural changes associated with productive infection. The abundance of early antigens in cells treated with Arildone was evidence for expression of the viral genome and this was confirmed by detection of immediate-early viral proteins in the presence of the drug. The results suggest that Arildone prevents the replication of human cytomegalovirus at a stage after virion uncoating but prior to viral DNA synthesis.

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1984-12-01
2024-04-25
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References

  1. Ashton W. T., Karkas J. D., Field A. K., Tolman R. L. 1982; Activation by thymidine kinase and potent antiherpetic activity of 2′-nor-2′-deoxyguanine (2′NDG). Biochemical and Biophysical Research Communications 108:1716–1721
    [Google Scholar]
  2. Balfour H. H., Bean B., Mitchell C. D., Sachs G. W., Boen J. R., Edelman K. 1982; Acyclovir in immunocompromised patients with cytomegalovirus disease. A controlled trial at one Institution. American Journal of Medicine 73:241–248
    [Google Scholar]
  3. Betts R. F. 1982; Cytomegalovirus infection in transplant patients. Progress in Medical Virology 28:44–64
    [Google Scholar]
  4. Blanton R. A., Trevethia M. J. 1981; Immunoprecipitation of virus-specific immediate-early and early polypeptides from cells lytically infected with human cytomegalovirus strain AD169. Virology 112:262–273
    [Google Scholar]
  5. Caliguiri L. A., McSharry J. J., Lawrence G. W. 1980; Effect of arildone on modifications of poliovirus in vitro. Virology 105:86–93
    [Google Scholar]
  6. Cameron J. M., Preston C. M. 1981; Comparison of the immediate early polypeptides of human cytomegalovirus isolates. Journal of General Virology 54:421–424
    [Google Scholar]
  7. Cheng Y. C., Huang E. S., Lin J. C., Mar E. C., Pagano J. S., Dutschman G. E., Grill S. P. 1983; Unique spectrum of activity of 9-[(1, 3-dihydroxy-2-propoxy)methyl]-guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1. Proceedings of the National Academy of Sciences, U.S.A 80:2767–2770
    [Google Scholar]
  8. De Marchi J. M. 1981; Human cytomegalovirus DNA: restriction enzyme cleavage maps and map locations for immediate-early, early and late RNAs. Virology 114:23–38
    [Google Scholar]
  9. Eriksson B., Oberg B., Wahren B. 1982; Pyrophosphate analogues as inhibitors of DNA polymerases of cytomegalovirus, herpes simplex virus and cellular origin. Biochimica et biophysica acta 696:115–123
    [Google Scholar]
  10. Furukawa T., Sakuma S., Plotkin S. A. 1976; Human cytomegalovirus infection of WI-38 cells stimulates mitochondrial DNA synthesis. Nature, London 262:414–416
    [Google Scholar]
  11. Gibson W. 1981; Immediate-early proteins of human cytomegalovirus strains AD169, Davis and Towne differ in electrophoretic mobility. Virology 112:350–354
    [Google Scholar]
  12. Gibson W. 1983; Protein counterparts of human and simian cytomegaloviruses. Virology 128:391–406
    [Google Scholar]
  13. Gluckman E., Lotsberg J., Deveigie A., Zhao X. M., Melo R., Gomez-Morales M., Nebout T., Mazeron M. C., Perol Y. 1983; Prophylaxis of herpes infections after bone-marrow transplantation by oral acyclovir. Lancet ii:706–708
    [Google Scholar]
  14. Goodheart C. R., McAllister R. M., Filbert J. E. 1964; Human cytomegalovirus, DNA synthesis and migration in infected cells studied autoradiographically. Virology 23:603–608
    [Google Scholar]
  15. Helgstrand E., Oberg B., Alenius S. 1979; Experimental studies on the antiherpetic agent phosphonoformic acid. Advances in Ophthalmology 38:276–280
    [Google Scholar]
  16. Huang E. S. 1975; Human cytomegalovirus. IV. Specific inhibition of virus induced DNA polymerase activity and viral DNA replication by phosphonoacetic acid. Journal of Virology 16:1560–1565
    [Google Scholar]
  17. Huang E. S., Chen S. T., Pagano J. S. 1973; Human cytomegalovirus. I. Purification and characterization of viral DNA. Journal of Virology 12:1473–1481
    [Google Scholar]
  18. Isom H. C. 1979; Stimulation of ornithine decarboxylase by human cytomegalovirus. Journal of General Virology 42:265–278
    [Google Scholar]
  19. Iwasaki Y., Furukawa T., Plotkin S. A., Koprowski H. 1973; Ultrastructural study on the sequence of human cytomegalovirus infection in human diploid cells. Archiv für die gesamte Virusforschung 40:311–324
    [Google Scholar]
  20. Jeffries D. J., Tyms A. S. 1983; Arildone, a potent inhibitor of cytomegalovirus replication. Lancet i:1214–1215
    [Google Scholar]
  21. Kim K. S., Sapienza V. J., Carp R. I. 1980; Antiviral activity of arildone on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrobial Agents and Chemotherapy 18:276–280
    [Google Scholar]
  22. Kuhrt M. F., Fancher M. J., Jasty V., Pancic F., Came P. E. 1979; Preliminary studies of the mode of action of arildone, a novel antiviral agent. Antimicrobial Agents and Chemotherapy 15:813–819
    [Google Scholar]
  23. Kung H. F., Ackerhalt R., Blau M. 1978; Uptake of TC-99M monophosphate complexes in bone and myocardial necrosis in animals. Journal of Nuclear Medicine 19:1027–1031
    [Google Scholar]
  24. Laemmli U. K. 1970; Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, London 227:680–685
    [Google Scholar]
  25. Lonsdale D. M. 1979; A rapid technique for distinguishing herpes simplex virus type 1 from type 2 by restriction-enzyme technology. Lancet i:849–852
    [Google Scholar]
  26. McAllister R. M., Straw R. M., Filbert J. E., Goodheart C. R. 1963; Human cytomegalovirus. Cytochemical observations of intracellular lesion development correlated with viral synthesis and release. Virology 19:521–531
    [Google Scholar]
  27. McAllister R. M., Filbert J. E., Goodheart C. R. 1967; Human cytomegalovirus. Studies on the mechanism of viral cytopathology and inclusion body formation. Proceedings of the Society for Experimental Biology and Medicine 124:932–937
    [Google Scholar]
  28. Macher A. M., Reichert C. M., Straus S. E., Longo D. L., Parrillo M. D., Lane H. C., Fauci A. S., Rook A. H., Manischewitz J. F., Quinnan G. V. 1983; Death in the AIDS patient: role of cytomegalovirus. New England Journal of Medicine 309:1454
    [Google Scholar]
  29. McKinlay M. A., Miralles J. V., Brisson C. J., Pancic F. 1982; Prevention of human poliovirus induced paralysis and death in mice by the novel antiviral agent arildone. Antimicrobial Agents and Chemotherapy 22:1022–1025
    [Google Scholar]
  30. McSharry J. J., Pancic F. 1982; Arildone: β-diketone. In Chemotherapy of Viral Infections Handbook of Experimental Pharmacology vol 61: pp 419–444 Edited by Came P. E., Caliguiri L. A. Berlin: Springer-Verlag;
    [Google Scholar]
  31. McSharry J. J., Pancic F. 1982; Arildone: β-diketone. In Chemotherapy of Viral Infections, Handbook of Experi-antiviral drug. Virology 97:307–315
    [Google Scholar]
  32. Mar E. C., Cheng Y. C., Huang E. S. 1983; Effect of 9-(1, 3-dihydroxy-2-propoxymethyl) guanine on human cytomegalovirus replication in vitro. Antimicrobial Agents and Chemotherapy 24:518–521
    [Google Scholar]
  33. Mar E. C., Patel P. C., Cheng Y. C., Fox J. J., Watanabe K. A., Huang E. S. 1984; Effects of certain nucleoside analogues on human cytomegalovirus replication in vitro. Journal of General Virology 65:47–53
    [Google Scholar]
  34. Marker S. C., Howard R. J., Simmons R. L., Kalis J. M., Connelly D. P., Najarian J. S., Balfour H. H. 1981; Cytomegalovirus infection: a quantitative prospective study of three hundred and twenty consecutive renal transplants. Surgery 89:660–671
    [Google Scholar]
  35. Meyers J. D., Flournoy N., Thomas E. D. 1982; Non-bacterial pneumonia after allogeneic marrow transplantation: a review of ten years experience. Reviews of Infectious Diseases 4:1119–1132
    [Google Scholar]
  36. Michelson S., Horodniceanu F., Kress M., Tardy-Panit M. 1979; Human cytomegalovirus-induced immediate early antigens: analysis in sodium dodecyl sulfate-polyacrylamide gel electrophoresis after immunoprecipitation. Journal of Virology 32:259–267
    [Google Scholar]
  37. Michelson-Fiske S., Horodniceanu F., Guillon J. C. 1977; Immediate-early antigens in human cytomegalovirus-infected cells. Nature, London 270:615–617
    [Google Scholar]
  38. Peckham C. S., Chin K. S., Coleman J. C., Henderson K., Hurley R., Preece P. M. 1983; Cytomegalovirus infection in pregnancy: preliminary findings from a prospective study. Lancet i:1352–1355
    [Google Scholar]
  39. Pegg A. E., McCann P. P. 1982; Polyamine metabolism and function. American Journal of Physiology 243:C212–C221
    [Google Scholar]
  40. Plotkin S. A., Starr S. E., Bryan C. K. 1982; In vitro and in vivo responses of cytomegalovirus to acyclovir. American Journal of Medicine 73:257–261
    [Google Scholar]
  41. Reynolds D. W. 1978; Development of early nuclear antigen in cytomegalovirus infected cells in the presence of RNA and protein synthesis inhibitors. Journal of General Virology 40:475–480
    [Google Scholar]
  42. Ryder T. A., Mackenzie M. L. 1981; The routine preparation of seminal fluid specimens for transmission electron microscopy. Journal of Clinical Pathology 34:1006–1009
    [Google Scholar]
  43. St Jeor S. C., Hutt R. 1977; Cell DNA replication as a function in the synthesis of human cytomegalovirus. Journal of General Virology 37:65–73
    [Google Scholar]
  44. Smee D. F., Martin J. C., Verheyden P. H., Matthews T. R. 1983; Anti-herpesvirus activity of the acyclic nucleoside 9-(1, 3-dihydroxy-2-propoxymethyl)guanine. Antimicrobial Agents and Chemotherapy 23:676–682
    [Google Scholar]
  45. Spector D. H., Hock L., Tamashiro J. C. 1982; Cleavage maps for human cytomegalovirus DNA strain AD 169 for restriction endonucleases EcoRI, BglII and Hind III. Journal of Virology 42:558–582
    [Google Scholar]
  46. Stenberg R. M., Thomsen D. R., Stinksi M. F. 1984; Structural analysis of the major immediate early gene of human cytomegalovirus. Journal of Virology 49:190–199
    [Google Scholar]
  47. Stern H. 1979; Intrauterine and perinatal cytomegalovirus infections. Journal of Antimicrobial Chemotherapy 5:81–85
    [Google Scholar]
  48. Stevens R. J., Jeffries D. J., Tyms A. S. 1984; Early protein marker for Towne cytomegalovirus vaccine. Lancet i 849
    [Google Scholar]
  49. Stinski M. 1978; Sequence of protein synthesis in cells infected by human cytomegalovirus: early and late virus-induced polypeptides. Journal of Virology 26:686–701
    [Google Scholar]
  50. Stinski M. F., Thomsen D. R., Rodriguez J. E. 1982; Synthesis of human cytomegalovirus-specified RNA and protein in interferon-treated cells at early times after infection. Journal of General Virology 60:261–270
    [Google Scholar]
  51. Stinski M. F., Thomsen D. R., Stenberg R. M., Goldstein L. C. 1983; Organization and expression of the immediate-early genes of human cytomegalovirus. Journal of Virology 46:1–14
    [Google Scholar]
  52. Tisdale M., Selway J. W. T. 1984; Effect of dichloroflavan on the stability and uncoating of rhinovirus type IB. Journal of Antimicrobial Chemotherapy 14:97–105
    [Google Scholar]
  53. Tyms A. S. 1983; Genome characterization of clinical isolates of human cytomegalovirus by restriction enzyme analysis. Medical Laboratory Sciences 40:81–83
    [Google Scholar]
  54. Tyms A. S., Williamson J. D. 1980; Polyamine metabolism in MRC-5 cells infected with human cytomegalovirus. Journal of General Virology 48:183–191
    [Google Scholar]
  55. Tyms A. S., Williamson J. D. 1982; Inhibitors of polyamine biosynthesis block human cytomegalovirus replication. Nature, London 297:690–691
    [Google Scholar]
  56. Tyms A. S., Scamans E. M., Williamson J. D. 1979; Polyamine metabolism in MRC5 cells infected with different herpesviruses. Biochemical and Biophysical Research Communications 86:312–318
    [Google Scholar]
  57. Tyms A. S., Scamans E. M., Naim H. M. 1981; The in vitro activity of acyclovir and related compounds against cytomegalovirus infections. Journal of Antimicrobial Chemotherapy 8:65–72
    [Google Scholar]
  58. Wade J. C., Hintz M., McGuffin R. W., Springmeyer S. C., Connor J. D., Meyers J. D. 1982; Treatment of cytomegalovirus pneumonia with high-dose acyclovir. American Journal of Medicine 73:249–256
    [Google Scholar]
  59. Wathen M. W., Stinski M. F. 1982; Temporal patterns of human cytomegalovirus transcription: mapping the viral RNAs synthesized at immediate-early, early and late times after infection. Journal of Virology 41:462–477
    [Google Scholar]
  60. Wathen M. W., Thomsen D. R., Stinski M. F. 1981; Temporal regulation of human cytomegalovirus: transcription at immediate-early and early times after infection. Journal of Virology 38:446–459
    [Google Scholar]
  61. Williamson J. D. 1976; The effect of methylglyoxal bis(guanylhydrazone) on vaccina virus replication. Biochemical and Biophysical Research Communications 73:120–126
    [Google Scholar]
  62. Williamson J. D., Cox P. 1968; Use of a new buffer in the culture of animal cells. Journal of General Virology 2:309–312
    [Google Scholar]
  63. Yeager A. S., Grumet F. C., Hafleigh E. B., Arvin A. M., Bradley J. S., Prober C. G. 1981; Prevention of transfusion-acquired cytomegalovirus infections in newborn infants. Journal of Pediatrics 98:281–287
    [Google Scholar]
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