Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses
Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses
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DOI：
10.1007/s00109-001-0300-8
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发表时间：
2002-04-01
影响因子：
4.7
通讯作者：
Huang, ES
中科院分区：
文献类型：
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作者：
Efferth, T;Marschall, M;Huang, ES
原发性和复发性巨细胞病毒感染的抗病毒治疗是为严重的表现而保留的，面临着一些限制。目前正在研究具有较低副作用和最低耐药频率的新药候选药物。在这里，我们证明了青蒿琥酯，一种抗疟疾药物具有很高的药理价值，具有抗病毒活性。在几种细胞系中证实了具有野生型表型的人巨细胞病毒复制的浓度依赖性抑制。用表达病毒变异的重组绿色荧光蛋白定量测定抑制作用。更昔洛韦敏感型和耐药型人巨细胞病毒的IC50值在相同范围内，分别为5.8+/-0.4 muM和6.9+/-0.2 muM。这表明它具有很强的抗病毒潜力，并且缺乏交叉抗性。青蒿琥酯的最佳抗病毒浓度与诱导细胞毒性浓度是可分离的。此外，来自三个属的病毒的复制被认为在不同程度上对青蒿琥酯敏感。这表明了一种与细胞激活途径相关的机制。在青蒿琥酯的作用下，两种病毒诱导的细胞转录因子Sp1和NF-kappaB的蛋白水平和DNA结合活性均明显降低。我们还分析了感染成纤维细胞中Sp1和NF-kappaB等因子激活所需的细胞信号激酶磷酸肌肽3激酶。在青蒿琥酯的作用下，磷酸肌肽3激酶的两种下游效应物Akt和p70S6K的磷酸化被显著抑制。因此，青蒿琥酯具有吸引人的抗病毒特性，这可能是基于对宿主细胞激酶级联反应的基本步骤的干扰。
Antiviral therapy of primary and recurrent infections with human cytomegalovirus is reserved for severe manifestations and faces several limitations. Presently candidates for novel drugs with lower adverse side effects and a minimized frequency of resistance formation are under investigation. Here we demonstrate that artesunate, an antimalaria drug with highly valuable pharmacological properties, possesses antiviral activity. A concentration-dependent inhibition of the replication of human cytomegaloviruses with wild-type phenotype was demonstrated in several cell lines. Inhibition was quantified using recombinant green fluorescent protein expressing virus variants. The IC50 values were in the same range for ganciclovir-sensitive and ganciclovir-resistant human cytomegalovirus, as calculated with 5.8+/-0.4 muM and 6.9+/-0.2 muM, respectively. This indicated a strong antiviral potential and a lack of cross-resistance. The optimal antiviral concentrations of artesunate were separable from those inducing cytotoxicity. In addition, the replication of viruses from three genera was seen to be artesunate-sensitive to varying degrees. This suggests a mechanism linked to cellular activation pathways. Both the protein levels and the DNA binding activity of the two virus-induced cellular transcription factors Sp1 and NF-kappaB were found to be markedly reduced in the presence of artesunate. We also analyzed the cellular signaling kinase phosphoinositide 3-kinase, required for the activation of factors such as Sp1 and NF-kappaB in infected fibroblasts. The phosphorylation of two downstream effectors of phosphoinositide 3-kinase, Akt and p70S6K, was markedly inhibited in the presence of artesunate. Thus, artesunate possesses attractive antiviral characteristics which are suggestively based on the interference with essential steps in the host cell kinase cascades.