Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus.
Acyclovir and vidarabine both exhibit anti-herpetic activity. Because different mechanisms of action of vidarabine and acyclovir have been reported, we analyzed their combined anti-herpetic activity on plaque formation of herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV) by isobolograms. The results indicate that acyclovir and vidarabine have a synergistic effect on wild type HSV-1, HSV-2, and VZV. The susceptibility of thymidine kinase-deficient HSV-1 to vidarabine was not affected by the presence of acyclovir, suggesting that phosphorylation of acyclovir is essential for synergism. The combined anti-HSV activity of acyclovir and vidarabine against phosphonoacetic acid-resistant HSV-1 with DNA polymerase mutation did not show synergism in contrast to that against wild-type herpesviruses. Alteration of the substrate specificity of viral DNA polymerase to acyclovir and vidarabine annihilated the synergism. Thus, the nature of their binding sites on DNA polymerase is important to the synergistic anti-herpesvirus activity of acyclovir and vidarabine.
Suzuki
Mikiko
M
Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Okuda
Tomoko
T
Shiraki
Kimiyasu
K
D000212:Acyclovir / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D017353:Gene Deletion; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D010746:Phosphonoacetic Acid / Q000494:pharmacology; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014740:Vidarabine / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D000998:Antiviral Agents; D014764:Viral Proteins; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D014740:Vidarabine; D010746:Phosphonoacetic Acid; D000212:Acyclovir