Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses.
Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses.
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DOI：
10.1016/j.antiviral.2013.06.014
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发表时间：
2013-09
影响因子：
7.6
通讯作者：
Liu, Yu-Tsueng
中科院分区：
文献类型：
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作者：
Chen, Hui-Wen;Cheng, Jenna Xiao;Liu, Ming-Tsan;King, Kevin;Peng, Ju-Yi;Zhang, Xin-Quan;Wang, Ching-Ho;Shresta, Sujan;Schooley, Robert T.;Liu, Yu-Tsueng
Diphyllin 抑制 MDCK 细胞和 A549 细胞的内体酸化。用二茶林治疗会改变细胞对流感病毒的易感性。 Diphyllin 具有广谱抗病毒活性。达菲林和其他药物的组合显示出增强的抗病毒作用。流感大流行对人类和动物构成严重威胁。传统的流感治疗方法包括两类针对病原体的抗病毒药物：M2离子通道阻滞剂（如金刚烷胺）和神经氨酸酶抑制剂（如奥司他韦）。对流感病毒感染机制的研究表明，内体酸化在促进病毒和内体膜之间的融合方面发挥着重要作用。该途径引发了对液泡 ATP 酶 (v-ATP 酶) 活性的研究，其作为流感病毒复制调节因子的作用已在广泛的全基因组筛选中得到验证。因此，阻断v-ATP酶活性提供了通过阻止内体和病毒粒子之间pH依赖性膜融合来干扰流感病毒感染的机会。本研究旨在通过基于细胞的检测，应用二茶林（一种被证明是一种新型 v-ATP 酶抑制剂的天然化合物）作为多种流感病毒株的潜在抗病毒药物。结果表明，二茶素通过抑制内体酸化来改变细胞对流感病毒的敏感性，从而干扰下游病毒复制，包括已知耐药菌株的复制。此外，针对宿主的二茶素与针对病原体的治疗药物（奥司他韦和金刚烷胺）的组合治疗显示出增强的体外抗病毒作用和细胞保护作用。
Diphyllin inhibits endosomal acidification in MDCK cells and A549 cells. Treatment with diphyllin alters the cellular susceptibility to the influenza virus. Diphyllin demonstrated a broad-spectrum antiviral activity. The combination of diphyllin and other drugs showed an enhanced antiviral effect. An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen-targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro.
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