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Cell line dependency for antiviral activity and in vivo efficacy of N-methanocarbathymidine against orthopoxvirus infections in mice.

Abstract
A novel carbocyclic thymidine analog, N-methanocarbathymidine [(N)-MCT], was evaluated for inhibition of orthopoxvirus infections. Efficacy in vitro was assessed by plaque reduction assays against wild-type and cidofovir-resistant strains of cowpox and vaccinia viruses in nine different cell lines. Minimal differences were seen in antiviral activity against wild-type and cidofovir-resistant viruses. (N)-MCT's efficacy was affected by the cell line used for assay, with 50% poxvirus-inhibitory concentrations in cells as follows: mouse=0.6-2.2 microM, rabbit=52-90 microM, monkey=87 to >1000 microM, and human=39-220 microM. Limited studies performed with carbocyclic thymidine indicated a similar cell line dependency for antiviral activity. (N)-MCT did not inhibit actively dividing uninfected cells at 1000 microM. The potency of (N)-MCT against an S-variant thymidine kinase-deficient vaccinia virus was similar to that seen against S-variant and wild-type viruses in mouse, monkey, and human cells, implicating a cellular enzyme in the phosphorylation of the compound. Mice were intranasally infected with cowpox and vaccinia viruses followed 24h later by intraperitoneal treatment with (N)-MCT (twice a day for 7 days) or cidofovir (once a day for 2 days). (N)-MCT treatment at 100 and 30 mg/kg/day resulted in 90 and 20% survival from cowpox virus infection, respectively, compared to 0% survival in the placebo group. Statistically significant reductions in lung virus titers on day 5 occurred in 10, 30, and 100mg/kg/day treated mice. These same doses were also active against a lethal vaccinia virus (WR strain) challenge, and protection was seen down to 10mg/kg/day against a lethal vaccinia virus (IHD strain) infection. Cidofovir (100mg/kg/day) protected animals from death in all three infections.
AuthorsDonald F Smee, Miles K Wandersee, Kevin W Bailey, Min-Hui Wong, Chung K Chu, Srinivas Gadthula, Robert W Sidwell
JournalAntiviral research (Antiviral Res) Vol. 73 Issue 1 Pg. 69-77 (Jan 2007) ISSN: 0166-3542 [Print] Netherlands
PMID16712967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antiviral Agents
  • (north)-methanocarbathymidine
  • Thymidine
Topics
  • Animals
  • Antiviral Agents (pharmacology, therapeutic use)
  • Cell Line
  • Cowpox (drug therapy, virology)
  • Cowpox virus (drug effects, growth & development)
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Rabbits
  • Respiratory Tract Infections (drug therapy, virology)
  • Thymidine (analogs & derivatives, pharmacology, therapeutic use)
  • Vaccinia (drug therapy, virology)
  • Vaccinia virus (drug effects, growth & development)

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