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

Nigel Bourne, F. J. Bravo, W. T. Ashton, L. C. Meurer, R. L. Tolman, J. D. Karkas, L. R. Stanberry

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2020-2024
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume36
Issue number9
StatePublished - 1992
Externally publishedYes

Fingerprint

9-((2-(hydroxymethyl)cyclohexyl)methyl)guanine
Herpes Genitalis
Investigational Therapies
Thymidine Kinase
Simplexvirus
Virus Diseases
Recurrence
Guinea Pigs
Diet
Human Herpesvirus 2
Water
Human Herpesvirus 1
Infection
Natural History
Pharmaceutical Preparations
Cerebral Cortex
Solubility
Inhibitory Concentration 50
Spinal Cord

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes. / Bourne, Nigel; Bravo, F. J.; Ashton, W. T.; Meurer, L. C.; Tolman, R. L.; Karkas, J. D.; Stanberry, L. R.

In: Antimicrobial Agents and Chemotherapy, Vol. 36, No. 9, 1992, p. 2020-2024.

Research output: Contribution to journalArticle

Bourne, Nigel ; Bravo, F. J. ; Ashton, W. T. ; Meurer, L. C. ; Tolman, R. L. ; Karkas, J. D. ; Stanberry, L. R. / Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes. In: Antimicrobial Agents and Chemotherapy. 1992 ; Vol. 36, No. 9. pp. 2020-2024.
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AU - Karkas, J. D.

AU - Stanberry, L. R.

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