Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1992 Sep;36(9):2020–2024. doi: 10.1128/aac.36.9.2020

Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes.

N Bourne 1, F J Bravo 1, W T Ashton 1, L C Meurer 1, R L Tolman 1, J D Karkas 1, L R Stanberry 1
PMCID: PMC192429  PMID: 1329638

Abstract

Herpes simplex virus (HSV)-coded thymidine kinase (TK) is important in efficient reactivation of latent infection. These studies were designed to investigate whether treatment of latently infected animals with a TK inhibitor altered the natural history of recurrent HSV disease. 9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) is a potent and selective nonsubstrate inhibitor of HSV TK which can suppress or delay reactivation of HSV-1 from latently infected cells in vitro without affecting viral replication. In an initial study, six female Hartley guinea pigs were treated with L-653,180 in their diet (25 mg/30 g of food) and water (300 mg/liter) for 7 days. Blood, urine, kidney, liver, spinal cord, and cerebral cortex specimens were collected. L-653,180 was detected in all specimens at concentrations which, although low, were higher than the in vitro 50% inhibitory concentration of the drug against HSV TK. In the second study, 20 female Hartley guinea pigs were randomized into two groups following recovery from primary genital HSV-2 infection. One group received L-653,180 in diet and water for 4 weeks beginning 21 days postinoculation. Animals were examined daily for recurrent lesions for 10 weeks. Treated animals experienced fewer recurrences during the treatment period but the results were not significantly different from results with controls. During the first 2-week posttreatment period, L-653,180-treated animals had significantly fewer recurrences than control animals (P = 0.02). Over the entire 10-week observation period, treated animals experienced fewer recurrences (P = 0.06). These results suggest that inhibitors of viral TK may be useful in limiting reactivation of latent virus and thus recurrent infections. In these experiments, the amount of drug that could be administered to the animals was limited by its poor solubility. Further studies with more potent and soluble inhibitors of HSV TK appear to be warranted.

Full text

PDF
2020

Selected References

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

  1. Coen D. M., Irmiere A. F., Jacobson J. G., Kerns K. M. Low levels of herpes simplex virus thymidine- thymidylate kinase are not limiting for sensitivity to certain antiviral drugs or for latency in a mouse model. Virology. 1989 Feb;168(2):221–231. doi: 10.1016/0042-6822(89)90261-4. [DOI] [PubMed] [Google Scholar]
  2. Coen D. M., Kosz-Vnenchak M., Jacobson J. G., Leib D. A., Bogard C. L., Schaffer P. A., Tyler K. L., Knipe D. M. Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4736–4740. doi: 10.1073/pnas.86.12.4736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Jamieson A. T., Gentry G. A., Subak-Sharpe J. H. Induction of both thymidine and deoxycytidine kinase activity by herpes viruses. J Gen Virol. 1974 Sep;24(3):465–480. doi: 10.1099/0022-1317-24-3-465. [DOI] [PubMed] [Google Scholar]
  4. Kaufman H. E., Varnell E. D., Cheng Y. C., Bobek M., Thompson H. W., Dutschman G. E. Suppression of ocular herpes recurrences by a thymidine kinase inhibitor in squirrel monkeys. Antiviral Res. 1991 Oct;16(3):227–232. doi: 10.1016/0166-3542(91)90002-9. [DOI] [PubMed] [Google Scholar]
  5. Keating M. R. Antiviral agents. Mayo Clin Proc. 1992 Feb;67(2):160–178. doi: 10.1016/s0025-6196(12)61319-6. [DOI] [PubMed] [Google Scholar]
  6. Kern E. R. Acyclovir treatment of experimental genital herpes simplex virus infections. Am J Med. 1982 Jul 20;73(1A):100–108. doi: 10.1016/0002-9343(82)90073-0. [DOI] [PubMed] [Google Scholar]
  7. Klein R. J. Initiation and maintenance of latent herpes simplex virus infections: the paradox of perpetual immobility and continuous movement. Rev Infect Dis. 1985 Jan-Feb;7(1):21–30. doi: 10.1093/clinids/7.1.21. [DOI] [PubMed] [Google Scholar]
  8. Leib D. A., Ruffner K. L., Hildebrand C., Schaffer P. A., Wright G. E., Coen D. M. Specific inhibitors of herpes simplex virus thymidine kinase diminish reactivation of latent virus from explanted murine ganglia. Antimicrob Agents Chemother. 1990 Jun;34(6):1285–1286. doi: 10.1128/aac.34.6.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Leist T. P., Sandri-Goldin R. M., Stevens J. G. Latent infections in spinal ganglia with thymidine kinase-deficient herpes simplex virus. J Virol. 1989 Nov;63(11):4976–4978. doi: 10.1128/jvi.63.11.4976-4978.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mayo D. R., Lucia H. L., Hsiung G. D. Effect of phosphonoformate on symptomatic genital herpes simplex virus type 2 infection of guinea pigs. Intervirology. 1983;19(1):26–32. doi: 10.1159/000149333. [DOI] [PubMed] [Google Scholar]
  11. Nsiah Y. A., Tolman R. L., Karkas J. D., Rapp F. Suppression of herpes simplex virus type 1 reactivation from latency by (+-)-9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) in vitro. Antimicrob Agents Chemother. 1990 Aug;34(8):1551–1555. doi: 10.1128/aac.34.8.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Stanberry L. R., Bernstein D. I., Kit S., Myers M. G. Genital reinfection after recovery from initial genital infection with herpes simplex virus type 2 in guinea pigs. J Infect Dis. 1986 Jun;153(6):1055–1061. doi: 10.1093/infdis/153.6.1055. [DOI] [PubMed] [Google Scholar]
  13. Stanberry L. R., Kern E. R., Richards J. T., Abbott T. M., Overall J. C., Jr Genital herpes in guinea pigs: pathogenesis of the primary infection and description of recurrent disease. J Infect Dis. 1982 Sep;146(3):397–404. doi: 10.1093/infdis/146.3.397. [DOI] [PubMed] [Google Scholar]
  14. Stanberry L. R., Kern E. R., Richards J. T., Overall J. C., Jr Recurrent genital herpes simplex virus infection in guinea pigs. Intervirology. 1985;24(4):226–231. doi: 10.1159/000149647. [DOI] [PubMed] [Google Scholar]
  15. Stanberry L. R., Kit S., Myers M. G. Thymidine kinase-deficient herpes simplex virus type 2 genital infection in guinea pigs. J Virol. 1985 Aug;55(2):322–328. doi: 10.1128/jvi.55.2.322-328.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Tenser R. B., Hay K. A., Edris W. A. Latency-associated transcript but not reactivatable virus is present in sensory ganglion neurons after inoculation of thymidine kinase-negative mutants of herpes simplex virus type 1. J Virol. 1989 Jun;63(6):2861–2865. doi: 10.1128/jvi.63.6.2861-2865.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Tenser R. B., Miller R. L., Rapp F. Trigeminal ganglion infection by thymidine kinase-negative mutants of herpes simplex virus. Science. 1979 Aug 31;205(4409):915–917. doi: 10.1126/science.224454. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES