Abstract
The hot-water extract of Geum japonicum has been shown to exhibit prophylactic and therapeutic anti-herpes simplex virus (HSV) activity in murine infection models. Eugeniin was purified as an anti-HSV compound from the extract and also was isolated from another herbal extract (Syzygium aromaticum) that had exhibited anti-HSV activity in mice. Thus the anti-HSV action of eugeniin was characterized. The effective concentration (5.0 μg/ml) for 50% plaque reduction of eugeniin for wild HSV type 1 (HSV-1) on Vero cells was 13.9-fold lower than its 50% cytotoxic concentration determined by a yield-reduction assay. Eugeniin also inhibited the growth of acyclovir-phosphonoacetic acid-resistant HSV-1, thymidine kinase-deficient HSV-1 and wild HSV type 2. Eugeniin as well as phosphonoacetic acid inhibited viral DNA and late viral protein syntheses in their infected Vero cells, but not cellular protein synthesis at its inhibitory concentrations. Purified HSV-1 DNA polymerase activity was inhibited by eugeniin noncompetitively with respect to dTTP. Its apparent Ki value for euginiin was 8.2- and 5.8-fold lower than theKi values of purified human DNA polymerases α and β, respectively. Thus one of the major target sites of inhibitory action of eugeniin is viral DNA synthesis; the inhibitory action for viral DNA polymerase activity was novel compared with anti-HSV nucleoside analogs.
Footnotes
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Send reprint requests to: Dr. Kimiyasu Shiraki, Department of Virology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930–01, Japan.
- Abbreviations:
- ACV
- acyclovir
- APr
- acyclovir-phosphonoacetic acid-resistant
- Ara-A
- 9-β-d-arabinofuranosyladenine
- BSA
- bovine serum albumin
- CC50
- 50% cytotoxic concentration
- DMSO
- dimethyl sulfoxide
- DTT
- dithiothreitol
- EC50
- effective concentrations for 50% plaque reduction
- EtOAc
- ethylacetate
- G. japonicum
- Geum japonicum Thunb
- HEL
- human embryonic lung
- HIV-1
- human immunodeficiency virus type 1
- HPLC
- high-performance liquid chromatography
- HSV
- herpes simplex virus
- HSV-1
- herpes simplex virus type 1
- HSV-2
- herpes simplex virus type 2
- MEM
- Eagle’s minimum essential medium
- PAA
- phosphonoacetic acid
- PFU
- plaque-forming units
- S. aromaticum
- Syzygium aromaticum (L.) MERR. et PERRY
- SDS
- sodium dodecyl sulfate
- TK−
- thymidine kinase-deficient
- UV
- ultraviolet
- Received April 7, 1997.
- Accepted October 3, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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