Nucleoside Inhibitors of Tick-Borne Encephalitis Virus
Nucleoside Inhibitors of Tick-Borne Encephalitis Virus
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DOI：
10.1128/aac.00807-15
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发表时间：
2015-09-01
影响因子：
4.9
通讯作者：
Ruzek, Daniel
中科院分区：
文献类型：
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作者：
Eyer, Ludek;Valdes, James J.;Ruzek, Daniel
蜱传脑炎病毒（TBEV）是欧洲和东北亚人类神经感染的主要原因。目前还没有治疗TBEV感染的抗病毒疗法。测试了一系列核苷类似物在猪肾细胞和人神经母细胞瘤细胞中抑制TBEV复制的能力。利用先进的计算方法模拟了三种核苷类似物与病毒聚合酶的相互作用。核苷类似物7-deaza-2 '-C-甲基腺苷（7-deaza-2'-CMA）、2 '-C-甲基腺苷（2'-CMA）和2 '-C-甲基胞苷（2'-CMC）抑制TBEV复制。这些化合物显示出对TBEV诱导的细胞病变效应、TBEV复制（对于7-脱氮-2 '-CMA，50%有效浓度[EC 50]为5.1 +/- 0.4 μ M，对于2'-CMA为7.1 +/- 1.2 μ M，对于2 '-CMC为14.2 +/- 1.9 μ M）和病毒抗原产生的剂量依赖性抑制。值得注意的是，2 '-CMC对猪肾细胞具有相对的细胞毒性（50%细胞毒性浓度[CC 50]类似于50 μ M）。2 '-CMA在细胞培养中的抗TBEV作用在处理后第3天逐渐减弱。7-Deaza-2 '-CMA没有显示出可检测的细胞毒性（CC_（50）> 50 μ M），并且在培养物中的抗病毒效果在处理后稳定> 6天。计算分子分析表明，与其他两种化合物相比，7-deaza-2 '-CMA在TBEV聚合酶的活性位点附近形成了一个大的簇。高抗病毒活性和低细胞毒性表明7-deaza-2 '-CMA是一种有希望的候选药物，可作为治疗TBEV感染的潜在药物进行进一步研究。
Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), and 2'-C-methylcytidine (2'-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50] of 5.1 +/- 0.4 mu M for 7-deaza-2'-CMA, 7.1 +/- 1.2 mu M for 2'-CMA, and 14.2 +/- 1.9 mu M for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of similar to 50 mu M). The anti-TBEV effect of 2'-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2'-CMA showed no detectable cellular toxicity (CC50 > 50 mu M), and the antiviral effect in culture was stable for > 6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2'-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2'-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.