Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects
Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects
复制标题
DOI：
10.1172/jci89857
复制
发表时间：
2017-04-03
影响因子：
15.9
通讯作者：
Einav, Shirit
中科院分区：
文献类型：
--
作者：
Bekerman, Elena;Neveu, Gregory;Einav, Shirit
全球健康受到新出现的病毒感染的威胁，这些感染在很大程度上缺乏有效的疫苗或疗法。针对被多个病毒利用的宿主路径可以提供广泛的解决方案。我们以前报道过宿主适配蛋白AP1和AP2的激酶调节蛋白AAK1和GAK在丙型肝炎病毒(HCV)感染中是必不可少的，但其潜在的机制和与其他病毒或体内感染的相关性尚不清楚。在这里，我们发现AP1和AP2与活细胞中的丙型肝炎病毒颗粒共交通。此外，我们发现包括登革热和埃博拉在内的多种病毒在进入和产生传染性病毒的过程中利用AAK1和GAK。在培养的细胞中，经批准的抑制AAK1或GAK活性的抗癌药物Sunitinib和erlotinib，或更具选择性的化合物处理，可以抑制丙型肝炎病毒和多种具有高耐药性屏障的无关RNA病毒在细胞内的传播。在登革热和埃博拉感染的小鼠模型中，舒尼替尼/埃洛替尼联合应用可预防发病率和死亡率。我们验证了孙尼替尼和厄洛替尼介导的抑制AAK1和GAK活性是抗病毒作用的重要机制。此外，我们还揭示了其他激酶靶标的潜在作用。这些发现促进了我们对病毒-宿主相互作用的理解，并为重新调整用途、以宿主为目标的方法对抗新出现的病毒建立了原则证据。
Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib-and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.