A thiopurine drug inhibits West Nile virus production in cell culture, but not in mice.
A thiopurine drug inhibits West Nile virus production in cell culture, but not in mice.
复制标题
硫嘌呤药物抑制细胞培养中的西尼罗河病毒的产生，但在小鼠中不抑制。
DOI：
10.1371/journal.pone.0026697
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bernard KA
中科院分区：
文献类型：
--
作者：
Lim PY;Keating JA;Hoover S;Striker R;Bernard KA
黄病毒属内的许多病毒在人类中引起重大疾病;然而，针对这些病毒的有效抗病毒药物目前不可用。我们以前已经表明，硫嘌呤药物，6-甲基巯基嘌呤核苷（6 MMPr），抑制细胞培养中黄病毒科家族内的远亲病毒的复制，包括牛病毒性腹泻病毒和丙型肝炎病毒复制子。在这里，我们进一步研究了6 MMPr对几种不同黄病毒的潜在抗病毒作用。在细胞培养中，6 MMPr以剂量依赖方式抑制黄热病毒、登革病毒-2（DENV-2）和西尼罗河病毒（WNV）的病毒产生，并且DENV-2对6 MMPr处理的敏感性显著高于WNV。然后，我们探索了使用6 MMPr作为抗WNV的免疫活性小鼠模型。在我们的小鼠模型中，每天一次用0.5 mg 6 MMPr治疗小鼠刚好低于毒性剂量，该剂量用于后续研究。小鼠在皮下接种WNV后立即用6 MMPr处理，连续8天。用6 MMPr治疗加重了WNV接种小鼠的体重减轻，但对死亡率没有显著影响。我们假设6 MMPr在中枢神经系统（CNS）中的生物利用度较低，并检查了6 MMPr预处理对外周和CNS中病毒载量的影响。用6 MMPr预处理对外周中的病毒血症或病毒滴度没有显著影响，但导致脑中的病毒载量显著更高，这表明6 MMPr的作用是组织依赖性的。总之，尽管在细胞培养物中是黄病毒的有效抑制剂，但6 MMPr对小鼠西尼罗河病无效;然而，需要进一步研究以降低这种潜在抗病毒药物的毒性和/或提高其生物利用度。
Many viruses within the Flavivirus genus cause significant disease in humans; however, effective antivirals against these viruses are not currently available. We have previously shown that a thiopurine drug, 6-methylmercaptopurine riboside (6MMPr), inhibits replication of distantly related viruses within the Flaviviridae family in cell culture, including bovine viral diarrhea virus and hepatitis C virus replicon. Here we further examined the potential antiviral effect of 6MMPr on several diverse flaviviruses. In cell culture, 6MMPr inhibited virus production of yellow fever virus, dengue virus-2 (DENV-2) and West Nile virus (WNV) in a dose-dependent manner, and DENV-2 was significantly more sensitive to 6MMPr treatment than WNV. We then explored the use of 6MMPr as an antiviral against WNV in an immunocompetent mouse model. Once a day treatment of mice with 0.5 mg 6MMPr was just below the toxic dose in our mouse model, and this dose was used in subsequent studies. Mice were treated with 6MMPr immediately after subcutaneous inoculation with WNV for eight consecutive days. Treatment with 6MMPr exacerbated weight loss in WNV-inoculated mice and did not significantly affect mortality. We hypothesized that 6MMPr has low bioavailability in the central nervous system (CNS) and examined the effect of pre-treatment with 6MMPr on viral loads in the periphery and CNS. Pre-treatment with 6MMPr had no significant effect on viremia or viral titers in the periphery, but resulted in significantly higher viral loads in the brain, suggesting that the effect of 6MMPr is tissue-dependent. In conclusion, despite being a potent inhibitor of flaviviruses in cell culture, 6MMPr was not effective against West Nile disease in mice; however, further studies are warranted to reduce the toxicity and/or improve the bioavailability of this potential antiviral drug.