Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106 - PubMed (original) (raw)

Justin G Julander et al. Antimicrob Agents Chemother. 2009 Jan.

Abstract

Treatment with the nucleoside analog T-1106 was previously shown to be effective in a hamster model of yellow fever virus (YFV) disease, even though it had only slight activity in cell culture. In the study described in this report, the activity of T-705, a chemically related compound currently undergoing clinical trials for the treatment of influenza (FDANews 4:1, 2007), was tested against YFV in cell culture and in the hamster model. The antiviral efficacy of T-705 in cell culture occurred at a concentration of 330 microM, which was more than threefold lower than the concentration at which T-1106 had antiviral efficacy, as determined by a virus yield reduction assay and confirmed by a luciferase-based ATP detection assay. Time-of-addition studies revealed that addition of T-705, T-1106, or ribavirin at 0, 4, 8, or 12 h after virus challenge was effective in inhibiting virus in Vero cells, suggesting that these three agents have similar mechanisms of action in cell culture. Because of its more potent activity in cell culture, it was anticipated that T-705 treatment of hamsters infected with YFV would result in protection from disease. Significant improvements in survival and disease parameters were seen in infected animals when T-705 was administered orally at a dose of 200 or 400 mg/kg of body weight per day when it was given twice a day for 8 days. Significant improvements were also observed with a dose of 400 mg/kg/day when treatment initiation was delayed as late as 3 days after virus inoculation. Although the dose of T-705 required for efficacy in hamsters is higher than that of T-1106 required for efficacy, T-705 treatment is effective in significantly improving disease parameters in YFV-infected hamsters, which may indicate its potential utility in the treatment of YFV disease in humans.

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Figures

FIG. 1.

FIG. 1.

Structures of T-705 and T-1106.

FIG. 2.

FIG. 2.

Time-of-addition study, in which T-705, T-1106, or ribavirin was added 0, 4, 8, 12, or 16 h after virus attachment. The supernatant was assayed for the initial level of virus production at 24 h after virus attachment by a virus yield reduction assay, and the results were compared with those of experiments in which no compound was added. Various doses of compound were tested at each treatment initiation time point, and the resulting CCID50s are shown. Tests were run in duplicate, and mean values are shown. Two independent experiments were conducted, and representative data are shown.

FIG. 3.

FIG. 3.

YFV RNA levels detected by QRT-PCR on 6 dpi from liver tissue of hamsters treated with various concentrations of T-705, T-1106, or ribavirin. mpk, mg/kg/day; ***, P < 0.001 compared with the results for the placebo group; **, P < 0.01 compared with the results for the placebo group.

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