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. 1992 May;36(5):934–937. doi: 10.1128/aac.36.5.934

Inactivators of herpes simplex virus ribonucleotide reductase: hematological profiles and in vivo potentiation of the antiviral activity of acyclovir.

T Spector 1, D C Lobe 1, M N Ellis 1, T A Blumenkopf 1, G M Szczech 1
PMCID: PMC188768  PMID: 1324641

Abstract

A1110U (BW 1110U81) is an inactivator of herpesvirus ribonucleotide reductases and a potentiator of the antiviral activity of acyclovir (ACV) (T. Spector, J. A. Harrington, R. W. Morrison, Jr., C. U. Lambe, D. J. Nelson, D. R. Averett, K. Biron, and P. A. Furman, Proc. Natl. Acad. Sci. USA 86:1051-1055, 1989) that was subsequently found to cause hematological toxicity at high oral doses in rats. Eleven structurally related inactivators of herpes simplex virus (HSV) ribonucleotide reductase were therefore tested in vivo for hematological toxicity and for potentiation of ACV. None of the novel ribonucleotide reductase inactivators was hematologically toxic to rats following oral dosing at 60 mg/kg/day for 30 days. Four of these inactivators statistically improved the antiviral topical potency of ACV on HSV type 1-infected nude mice. A promising compound, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone (BW 348U87), was studied more extensively in two in vivo models: dorsum-infected athymic nude mice and snout-infected hairless mice. BW 348U87 significantly potentiated the antiviral activity of ACV against all virus strains tested, i.e., wild-type (ACV-sensitive) HSV type 1 and HSV type 2 strains and three mutant (ACV-resistant) HSV type 1 strains. The latter included a virus expressing a DNA polymerase resistant to inhibition by ACV triphosphate, a virus deficient in thymidine kinase (the enzyme responsible for phosphorylating ACV), and a virus expressing an altered thymidine kinase, which catalyzes the normal phosphorylation of thymidine but not of ACV. BW 348U87 and ACV are currently being developed as a combination topical therapy for cutaneous herpes infections.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ellis M. N., Lobe D. C., Spector T. Synergistic therapy by acyclovir and A1110U for mice orofacially infected with herpes simplex viruses. Antimicrob Agents Chemother. 1989 Oct;33(10):1691–1696. doi: 10.1128/aac.33.10.1691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Furman P. A., Lambe C. U., Nelson D. J. Effect of acyclovir on the deoxyribonucleoside triphosphate pool levels in Vero cells infected with herpes simplex virus type 1. Am J Med. 1982 Jul 20;73(1A):14–17. doi: 10.1016/0002-9343(82)90056-0. [DOI] [PubMed] [Google Scholar]
  3. Holmgren A. Regulation of ribonucleotide reductase. Curr Top Cell Regul. 1981;19:47–76. doi: 10.1016/b978-0-12-152819-5.50019-1. [DOI] [PubMed] [Google Scholar]
  4. Hunting D., Henderson J. F. Models of the regulation of ribonucleotide reductase and their evaluation in intact mammalian cells. CRC Crit Rev Biochem. 1982;13(4):325–348. doi: 10.3109/10409238209108713. [DOI] [PubMed] [Google Scholar]
  5. Karlsson A., Harmenberg J. Effects of ribonucleotide reductase inhibition on pyrimidine deoxynucleotide metabolism in acyclovir-treated cells infected with herpes simplex virus type 1. Antimicrob Agents Chemother. 1988 Jul;32(7):1100–1102. doi: 10.1128/aac.32.7.1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Lobe D. C., Spector T., Ellis M. N. Synergistic topical therapy by acyclovir and A1110U for herpes simplex virus induced zosteriform rash in mice. Antiviral Res. 1991 Feb;15(2):87–100. doi: 10.1016/0166-3542(91)90027-o. [DOI] [PubMed] [Google Scholar]
  7. Porter D. J., Harrington J. A., Spector T. Herpes simplex virus type 1 ribonucleotide reductase: selective and synergistic inactivation by A1110U and its iron complex. Biochem Pharmacol. 1990 Feb 15;39(4):639–646. doi: 10.1016/0006-2952(90)90140-g. [DOI] [PubMed] [Google Scholar]
  8. Reardon J. E., Spector T. Acyclovir: mechanism of antiviral action and potentiation by ribonucleotide reductase inhibitors. Adv Pharmacol. 1991;22:1–27. doi: 10.1016/s1054-3589(08)60031-9. [DOI] [PubMed] [Google Scholar]
  9. Reardon J. E., Spector T. Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate. J Biol Chem. 1989 May 5;264(13):7405–7411. [PubMed] [Google Scholar]
  10. Spector T., Averett D. R., Nelson D. J., Lambe C. U., Morrison R. W., Jr, St Clair M. H., Furman P. A. Potentiation of antiherpetic activity of acyclovir by ribonucleotide reductase inhibition. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4254–4257. doi: 10.1073/pnas.82.12.4254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Spector T., Harrington J. A., Morrison R. W., Jr, Lambe C. U., Nelson D. J., Averett D. R., Biron K., Furman P. A. 2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1051–1055. doi: 10.1073/pnas.86.3.1051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Spector T., Harrington J. A., Porter D. J. Herpes and human ribonucleotide reductases. Inhibition by 2-acetylpyridine 5-[(2-chloroanilino)-thiocarbonyl]-thiocarbonohydrazone (348U87). Biochem Pharmacol. 1991 Jun 21;42(1):91–96. doi: 10.1016/0006-2952(91)90685-x. [DOI] [PubMed] [Google Scholar]
  13. Spector T. Inhibition of ribonucleotide reductases encoded by herpes simplex viruses. Pharmacol Ther. 1985;31(3):295–302. doi: 10.1016/0163-7258(85)90027-0. [DOI] [PubMed] [Google Scholar]
  14. Thelander L., Reichard P. Reduction of ribonucleotides. Annu Rev Biochem. 1979;48:133–158. doi: 10.1146/annurev.bi.48.070179.001025. [DOI] [PubMed] [Google Scholar]

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