1-Benzyl-3-cetyl-2-methylimidazolium Iodide (NH125) Is a Broad-Spectrum Inhibitor of Virus Entry with Lysosomotropic Features.
1-Benzyl-3-cetyl-2-methylimidazolium Iodide (NH125) Is a Broad-Spectrum Inhibitor of Virus Entry with Lysosomotropic Features.
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DOI：
10.3390/v10060306
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发表时间：
2018-06-05
期刊：
影响因子：
--
通讯作者：
Zimmer G
中科院分区：
文献类型：
--
作者：
Moeschler S;Locher S;Zimmer G
细胞激酶对许多负链RNA病毒的转录/复制至关重要，并可能作为抗病毒治疗的靶点。在这项研究中，包含80个激酶抑制剂的文库被筛选用于抗水泡性口炎病毒（VSV）（弹状病毒科的原型成员）的抗病毒活性。1-苄基-3-十六烷基-2-甲基咪唑碘化铵（NH 125），一种真核细胞延伸因子2（eEF 2）激酶的抑制剂，可显著抑制编码荧光素酶报告基因的单循环VSV的进入。处理病毒颗粒对病毒进入的影响很小，表明该化合物主要作用于宿主细胞而不是病毒。因此，当病毒在药物存在下传代时，未检测到抗性突变病毒。出乎意料的是，NH 125导致eEF 2的磷酸化增强，而不是减少，然而，它并没有显着影响细胞蛋白质合成。与此相反，NH 125显示亲溶酶体功能，并显示与N-十二烷基咪唑，一个已知的亲溶酶体剂的结构相似性。相关的烷基化咪唑鎓化合物也表现出抗病毒活性，这与烷基的长度密切相关。除VSV外，NH 125还抑制VSV假型的感染，所述假型含有已知以pH依赖性方式进入细胞的病毒的包膜糖蛋白，即禽流感病毒（H5 N1）、埃博拉病毒和拉沙病毒。总之，我们确定了一种烷基化咪唑鎓化合物，其抑制几种病毒的进入，不是因为先前假定的eEF 2激酶的抑制，而是最有可能是因为其亲溶酶体性质。
Cellular kinases are crucial for the transcription/replication of many negative-strand RNA viruses and might serve as targets for antiviral therapy. In this study, a library comprising 80 kinase inhibitors was screened for antiviral activity against vesicular stomatitis virus (VSV), a prototype member of the family Rhabdoviridae. 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125), an inhibitor of eukaryotic elongation factor 2 (eEF2) kinase, significantly inhibited entry of single-cycle VSV encoding a luciferase reporter. Treatment of virus particles had only minimal effect on virus entry, indicating that the compound primarily acts on the host cell rather than on the virus. Accordingly, resistant mutant viruses were not detected when the virus was passaged in the presence of the drug. Unexpectedly, NH125 led to enhanced, rather than reduced, phosphorylation of eEF2, however, it did not significantly affect cellular protein synthesis. In contrast, NH125 revealed lysosomotropic features and showed structural similarity with N-dodecylimidazole, a known lysosomotropic agent. Related alkylated imidazolium compounds also exhibited antiviral activity, which was critically dependent on the length of the alkyl group. Apart from VSV, NH125 inhibited infection by VSV pseudotypes containing the envelope glycoproteins of viruses that are known to enter cells in a pH-dependent manner, i.e. avian influenza virus (H5N1), Ebola virus, and Lassa virus. In conclusion, we identified an alkylated imidazolium compound which inhibited entry of several viruses not because of the previously postulated inhibition of eEF2 kinase but most likely because of its lysosomotropic properties.
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影响因子：
3.8
作者：
Hoffmann, Markus;Wu, Yuan-Ju;Zimmer, Gert
通讯作者：
Zimmer, Gert
影响因子：
5.5
作者：
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DOI：
10.1016/j.bbapap.2015.04.011
发表时间：
2015-10-01
影响因子：
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作者：
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5.4
作者：
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影响因子：
4.4
作者：
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