Activity of T-705 in a Hamster Model of Yellow Fever Virus Infection in Comparison with That of a Chemically Related Compound, T-1106
Activity of T-705 in a Hamster Model of Yellow Fever Virus Infection in Comparison with That of a Chemically Related Compound, T-1106
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DOI：
10.1128/aac.01074-08
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发表时间：
2009-01-01
影响因子：
4.9
通讯作者：
Furuta, Yousuke
中科院分区：
文献类型：
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作者：
Julander, Justin G.;Shafer, Kristiina;Furuta, Yousuke
核苷类似物T-1106的治疗先前已被证明在黄热病病毒（YFV）疾病的仓鼠模型中是有效的，尽管它在细胞培养中只有轻微的活性。在本报告所述的研究中，在细胞培养物和仓鼠模型中测试了T-705（一种目前正在进行治疗流感临床试验的化学相关化合物）对YFV的活性（FDANews 4：1，2007）。T-705在细胞培养物中的抗病毒效力发生在330 μ M的浓度下，该浓度比T-1106具有抗病毒效力的浓度低三倍以上，如通过病毒产率降低测定所确定的，并通过基于腺苷三磷酸酶的ATP检测测定所证实的。添加时间研究显示，在病毒攻击后0、4、8或12 h添加T-705、T-1106或利巴韦林可有效抑制Vero细胞中的病毒，表明这三种药物在细胞培养中具有相似的作用机制。由于T-705在细胞培养中的活性更强，因此预期T-705对感染YFV的仓鼠的治疗将导致疾病的保护。当以200或400 mg/kg体重/天的剂量经口给予T-705，每天两次，持续8天时，在感染动物中观察到存活率和疾病参数的显著改善。当给药开始延迟至病毒接种后3天时，在400 mg/kg/天剂量下也观察到显著改善。尽管T-705在仓鼠中的有效性所需的剂量高于T-1106的有效性所需的剂量，但T-705治疗在显著改善YFV感染的仓鼠中的疾病参数方面是有效的，这可能表明其在人类YFV疾病治疗中的潜在效用。
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 mu M, 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.