Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA
Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA
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DOI：
10.1006/viro.2002.1685
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发表时间：
2002-12-20
期刊：
影响因子：
3.7
通讯作者：
Harris, E
中科院分区：
文献类型：
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作者：
Diamond, MS;Zachariah, M;Harris, E
登革热是一种具有全球重要性的蚊媒病毒性疾病，目前尚无抗病毒治疗方法。我们评估了霉酚酸（MPA）（一种目前用作免疫抑制剂的药物）抑制登革热病毒（DV）抗原表达、RNA复制和病毒产生的能力。药理学浓度的MPA可有效阻断DV感染，将感染细胞的百分比降低99%，并将分泌的病毒水平降低100万倍。用四种肝癌细胞系和不同的黄病毒（包括最近分离的西尼罗病毒）重现了结果。通过实验来确定IMPA在病毒生命周期中消除感染的阶段。病毒感染的早期步骤，如病毒进入和核衣壳脱壳，并不是IMPA作用的主要目标，因为当裸DV RNA直接转染到细胞中时，IMPA的抑制作用仍然保留。生物合成标记实验表明，MPA不阻断病毒翻译的初始阶段，但在扩增阶段干扰病毒蛋白的合成。定量RT-PCR显示，MPA在感染过程中阻止了病毒正链和负链RNA的积累。我们得出结论，IMPA通过阻止病毒RNA的合成和积累来抑制黄病毒感染。(C) 2002 Elsevier Science （USA）。
Dengue fever is a mosquito-borne viral disease of global importance with no available antiviral therapy. We assessed the ability of mycophenolic acid (MPA), a drug currently used as an immunosuppressive agent, to inhibit dengue virus (DV) antigen expression, RNA replication, and virus production. Pharmacological concentrations of MPA effectively blocked DV infection, decreasing the percentage of infected cells by 99% and the levels of secreted virus by up to a millionfold. Results were reproduced with four hepatoma cell lines and different flaviviruses, including a recent West Nile virus isolate. Experiments were performed to define the stage in the viral lifecycle at which IMPA abrogates infection. Early steps in viral infection, such as viral entry and nucleocapsid uncoating, were not the primary targets of IMPA action since its inhibitory effect was retained when naked DV RNA was transfected directly into cells. Biosynthetic labeling experiments showed that MPA did not block the initial phase of viral translation but did interfere with viral protein synthesis in the amplification phase. Quantitative RT-PCR demonstrated that MPA prevented the accumulation of viral positive- and negative-strand RNA as the infection proceeded. We conclude that IMPA inhibits flavivirus infection by preventing synthesis and accumulation of viral RNA. (C) 2002 Elsevier Science (USA).