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. 1985 Aug;28(2):240–245. doi: 10.1128/aac.28.2.240

Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses.

V R Freitas, D F Smee, M Chernow, R Boehme, T R Matthews
PMCID: PMC180226  PMID: 3010840

Abstract

The activities of the purine acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) against two human and five animal strains of cytomegalovirus were compared with those of acyclovir. DHPG was significantly more active than acyclovir against all but one (mouse cytomegalovirus) of the strains tested, with 50% effective doses ranging from 5 to 13 microM, as determined by plaque reduction assays in human embryonic lung (MRC-5) and human embryonic tonsil cells. Both DHPG and acyclovir inhibited virus replication at concentrations considerably lower than those necessary to inhibit cell proliferation. In mode-of-action studies, the triphosphates of DHPG and acyclovir inhibited human cytomegalovirus DNA polymerase. DHPG phosphorylation to the active triphosphate was enhanced in infected cells; however, this enzymatic activity was unrelated to thymidine kinase. In animal studies, DHPG was slightly more effective than acyclovir in reducing mouse cytomegalovirus-induced mortality.

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Selected References

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  1. Biron K. K., Stanat S. C., Sorrell J. B., Fyfe J. A., Keller P. M., Lambe C. U., Nelson D. J. Metabolic activation of the nucleoside analog 9-[( 2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2473–2477. doi: 10.1073/pnas.82.8.2473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Burns W. H., Wingard J. R., Bender W. J., Saral R. Thymidine kinase not required for antiviral activity of acyclovir against mouse cytomegalovirus. J Virol. 1981 Sep;39(3):889–893. doi: 10.1128/jvi.39.3.889-893.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burns W. H., Wingard J. R., Sandford G. R., Bender W. J., Saral R. Acyclovir in mouse cytomegalovirus infections. Am J Med. 1982 Jul 20;73(1A):118–124. doi: 10.1016/0002-9343(82)90076-6. [DOI] [PubMed] [Google Scholar]
  4. Cheng Y. C., Dutschman G., Fox J. J., Watanabe K. A., Machida H. Differential activity of potential antiviral nucleoside analogs on herpes simplex virus-induced and human cellular thymidine kinases. Antimicrob Agents Chemother. 1981 Sep;20(3):420–423. doi: 10.1128/aac.20.3.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cheng Y. C., Grill S. P., Dutschman G. E., Frank K. B., Chiou J. F., Bastow K. F., Nakayama K. Effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new antiherpesvirus compound, on synthesis of macromolecules in herpes simplex virus-infected cells. Antimicrob Agents Chemother. 1984 Sep;26(3):283–288. doi: 10.1128/aac.26.3.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cheng Y. C., Huang E. S., Lin J. C., Mar E. C., Pagano J. S., Dutschman G. E., Grill S. P. 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. Proc Natl Acad Sci U S A. 1983 May;80(9):2767–2770. doi: 10.1073/pnas.80.9.2767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Choi Y. C., Hsiung G. D. Cytomegalovirus infection in guinea pigs. II. Transplacental and horizontal transmission. J Infect Dis. 1978 Aug;138(2):197–202. doi: 10.1093/infdis/138.2.197. [DOI] [PubMed] [Google Scholar]
  8. Colacino J. M., Lopez C. Efficacy and selectivity of some nucleoside analogs as anti-human cytomegalovirus agents. Antimicrob Agents Chemother. 1983 Oct;24(4):505–508. doi: 10.1128/aac.24.4.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Datta A. K., Pagano J. S. Phosphorylation of acyclovir in vitro in activated Burkitt somatic cell hybrids. Antimicrob Agents Chemother. 1983 Jul;24(1):10–14. doi: 10.1128/aac.24.1.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Estes J. E., Huang E. S. Stimulation of cellular thymidine kinases by human cytomegalovirus. J Virol. 1977 Oct;24(1):13–21. doi: 10.1128/jvi.24.1.13-21.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Field A. K., Davies M. E., DeWitt C., Perry H. C., Liou R., Germershausen J., Karkas J. D., Ashton W. T., Johnston D. B., Tolman R. L. 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4139–4143. doi: 10.1073/pnas.80.13.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Furman P. A., de Miranda P., St Clair M. H., Elion G. B. Metabolism of acyclovir in virus-infected and uninfected cells. Antimicrob Agents Chemother. 1981 Oct;20(4):518–524. doi: 10.1128/aac.20.4.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fyfe J. A., Keller P. M., Furman P. A., Miller R. L., Elion G. B. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J Biol Chem. 1978 Dec 25;253(24):8721–8727. [PubMed] [Google Scholar]
  14. Griffith B. P., Hsiung G. D. Cytomegalovirus infection in guinea pigs. IV. Maternal infection at different stages of gestation. J Infect Dis. 1980 Jun;141(6):787–793. doi: 10.1093/infdis/141.6.787. [DOI] [PubMed] [Google Scholar]
  15. Hsiung G. D., Choi Y. C., Bia F. Cytomegalovirus infection in guinea pigs. I. Viremia during acute primary and chronic persistent infection. J Infect Dis. 1978 Aug;138(2):191–196. doi: 10.1093/infdis/138.2.191. [DOI] [PubMed] [Google Scholar]
  16. Kelsey D. K., Kern E. R., Overall J. C., Jr, Glasgow L. A. Effect of cytosine arabinoside and 5-iodo-2'-deoxyuridine on a cytomegalovirus infection in newborn mice. Antimicrob Agents Chemother. 1976 Mar;9(3):458–464. doi: 10.1128/aac.9.3.458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Mar E. C., Cheng Y. C., Huang E. S. Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on human cytomegalovirus replication in vitro. Antimicrob Agents Chemother. 1983 Oct;24(4):518–521. doi: 10.1128/aac.24.4.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mar E. C., Chiou J. F., Cheng Y. C., Huang E. S. Inhibition of cellular DNA polymerase alpha and human cytomegalovirus-induced DNA polymerase by the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine. J Virol. 1985 Mar;53(3):776–780. doi: 10.1128/jvi.53.3.776-780.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Martin J. C., Dvorak C. A., Smee D. F., Matthews T. R., Verheyden J. P. 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent. J Med Chem. 1983 May;26(5):759–761. doi: 10.1021/jm00359a023. [DOI] [PubMed] [Google Scholar]
  21. Meijer H., Bruggeman C. A., Dormans P. H., van Boven C. P. Rat cytomegalovirus induces cellular purine and pyrimidine nucleoside kinases in rat embryo fibroblasts and TK- rat-2 cells. Correlations with the antiviral activity of Acyclovir. Arch Virol. 1985;83(3-4):181–194. doi: 10.1007/BF01309915. [DOI] [PubMed] [Google Scholar]
  22. Schaeffer H. J., Beauchamp L., de Miranda P., Elion G. B., Bauer D. J., Collins P. 9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature. 1978 Apr 13;272(5654):583–585. doi: 10.1038/272583a0. [DOI] [PubMed] [Google Scholar]
  23. Selgrade M. K., Nedrud J. G., Collier A. M., Gardner D. E. Effects of cell source, mouse strain, and immunosuppressive treatment on production of virulent and attenuated murine cytomegalovirus. Infect Immun. 1981 Sep;33(3):840–847. doi: 10.1128/iai.33.3.840-847.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smee D. F., Boehme R., Chernow M., Binko B. P., Matthews T. R. Intracellular metabolism and enzymatic phosphorylation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus-infected and uninfected cells. Biochem Pharmacol. 1985 Apr 1;34(7):1049–1056. doi: 10.1016/0006-2952(85)90608-2. [DOI] [PubMed] [Google Scholar]
  25. Smee D. F., Martin J. C., Verheyden J. P., Matthews T. R. Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob Agents Chemother. 1983 May;23(5):676–682. doi: 10.1128/aac.23.5.676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Smith K. O., Galloway K. S., Kennell W. L., Ogilvie K. K., Radatus B. K. A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2. Antimicrob Agents Chemother. 1982 Jul;22(1):55–61. doi: 10.1128/aac.22.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. St Clair M. H., Miller W. H., Miller R. L., Lambe C. U., Furman P. A. Inhibition of cellular alpha DNA polymerase and herpes simplex virus-induced DNA polymerases by the triphosphate of BW759U. Antimicrob Agents Chemother. 1984 Feb;25(2):191–194. doi: 10.1128/aac.25.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tocci M. J., Livelli T. J., Perry H. C., Crumpacker C. S., Field A. K. Effects of the nucleoside analog 2'-nor-2'-deoxyguanosine on human cytomegalovirus replication. Antimicrob Agents Chemother. 1984 Feb;25(2):247–252. doi: 10.1128/aac.25.2.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tyms A. S., Scamans E. M., Naim H. M. The in vitro activity of acyclovir and related compounds against cytomegalovirus infections. J Antimicrob Chemother. 1981 Jul;8(1):65–72. doi: 10.1093/jac/8.1.65. [DOI] [PubMed] [Google Scholar]

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