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A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells

Nature volume 358, pages 162–164 (1992)Cite this article

A Correction to this article was published on 30 December 1993

An Erratum to this article was published on 03 September 1992

Abstract

HUMAN cytomegalovirus (HCMV) is a major pathogen in immunosuppressed individuals, including patients with acquired immune deficiency syndrome. The nucleoside analogue ganciclovir (9-(l,3-dihydroxy-2-propoxymethyl)-guanine) is one of the few drugs available to treat HCMV infections, but resistant virus is a growing problem in the clinic1 and there is a critical need for new drugs. The study of ganciclovir-resistant mutants has indicated that the selective action of ganciclovir depends largely on virus-controlled phosphorylation in HCMV-infected cells2–5. The enzyme(s) responsible have not been identified. Here we report that the HCMV gene UL97, whose predicted product shares regions of homology with protein kinases, guanylyl cyclase and bacterial phosphotransferases6–8, controls phosphorylation of ganciclovir in HCMV-infected cells. A four-amino-acid deletion of UL97 in a conserved region, which in cyclic AMP-dependent protein kinase participates in substrate recognition9, causes impaired ganciclovir phosphorylation. The implications of these results for antiviral drug development and drug resistance are discussed.

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References

  1. Drew, W. L. et al. J. infect Dis. 163, 716–719 (1991).

    Article  CAS  Google Scholar 

  2. Biron, K. K. et al. Proc. natn. Acad. Sci. U.S.A. 82, 2473–2477 (1985).

    Article  CAS  ADS  Google Scholar 

  3. Freitas, V. R., Smee, D. F., Chernow, M., Boehme, R. & Matthews, T. R. Antimicrob. Ag. Chemother. 28, 240–245 (1985).

    Article  CAS  Google Scholar 

  4. Biron, K. K. et al. Proc. natn. Acad. Sci. U.S.A. 83, 8769–8773 (1986).

    Article  CAS  ADS  Google Scholar 

  5. Stanat, S. C. et al. Antimicrob. Ag. Chemother. 35, 2191–2197 (1991).

    Article  CAS  Google Scholar 

  6. Chee, M. S., Lawrence, G. L. & Barrell, B. G. J. gen. Virol. 70, 1151–1160 (1989).

    Article  CAS  Google Scholar 

  7. Brenner, S. Nature 329, 21 (1987).

    Article  CAS  ADS  Google Scholar 

  8. Singh, S. et al. Nature 334, 708–712 (1988).

    Article  CAS  ADS  Google Scholar 

  9. Knighton, D. R. et al. Science 253, 414–420 (1991).

    Article  CAS  ADS  Google Scholar 

  10. McGeoch, D. J. et al. J. gen. Virol. 69, 1531–1574 (1988).

    Article  CAS  Google Scholar 

  11. Davison, A. J. & Scott, J. E. J. gen. Virol. 67, 1759–1816 (1986).

    Article  CAS  Google Scholar 

  12. Baer, R. et al. Nature 310, 207–211 (1984).

    Article  CAS  ADS  Google Scholar 

  13. Smith, R. F. & Smith, T. F. J. Virol. 63, 450–455 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hanks, S. K., Quinn, A. M. & Hunter, T. Science 241, 42–52 (1988).

    Article  CAS  ADS  Google Scholar 

  15. Agut, H. et al. Res. Virol. 140, 219–228 (1989).

    Article  CAS  Google Scholar 

  16. Di Luca, D., Katsafanas, G., Schrimer, E. C., Balachandran, N. & Frenkel, N. Virology 175, 199–210 (1990).

    Article  CAS  Google Scholar 

  17. Fyfe, J. A., Keller, P. M., Furman, P. A., Miller, R. L. & Elion, G. B. J. biol Chem. 253, 8721–8727 (1978).

    CAS  PubMed  Google Scholar 

  18. Chee, M. S. et al. Curr. Top. Microbiol. Immun. 154, 125–169 (1990).

    CAS  Google Scholar 

  19. Mar, E.-C., Patel, P. C. & Huang, E.-S. J. gen. Virol. 57, 149–156 (1981).

    Article  CAS  Google Scholar 

  20. Michelson, S., Tardy-Panit, M. & Barzo, O. Virology 134, 259–268 (1984).

    Article  CAS  Google Scholar 

  21. Roby, C. & Gibson, W. J. Virol. 59, 714–727 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Britt, W. J. & Auger, D. J. Virol. 59, 185–188 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Somogyi, T., Michelson, S. & Masse, M.-J., O. Virology 174, 276–285 (1990).

    Article  CAS  Google Scholar 

  24. Littler, E., Stuart, A. D. & Chee, M. S. Nature 358, 160–162 (1992).

    Article  CAS  ADS  Google Scholar 

  25. Lau, Y.-F. & Kan, Y. W. Proc. natn. Acad. Sci. U.S.A. 80, 5225–5229 (1983).

    Article  CAS  ADS  Google Scholar 

  26. Fleckenstein, B., Muller, I. & Collins, J. Gene 18, 39–46 (1982).

    Article  CAS  Google Scholar 

  27. Fyfe, J. A., McKee, S. A. & Keller, P. M. Molec. Pharmac. 24, 316–323 (1983).

    CAS  Google Scholar 

  28. Shoji, S. et al. Proc. natn. Acad. Sci. U.S.A. 78, 848–851 (1981).

    Article  CAS  ADS  Google Scholar 

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    V. Sullivan & D. M. Coen

  2. Division of Virology, Burroughs Wellcome Company, Research Triangle Park, North Carolina, 27709, USA

    C. L. Talarico, S. C. Stanat, M. Davis & K. K. Biron

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  1. V. Sullivan
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  2. C. L. Talarico
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  3. S. C. Stanat
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  4. M. Davis
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  5. D. M. Coen
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  6. K. K. Biron
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Sullivan, V., Talarico, C., Stanat, S. et al. A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature 358, 162–164 (1992). https://doi.org/10.1038/358162a0

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