Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.
Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.
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DOI：
10.1016/j.virol.2017.04.001
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发表时间：
2017-07
期刊：
影响因子：
3.7
通讯作者：
Aida Y
中科院分区：
文献类型：
--
作者：
Chutiwitoonchai N;Mano T;Kakisaka M;Sato H;Kondoh Y;Osada H;Kotani O;Yokoyama M;Sato H;Aida Y
利用我们前期的高通量筛选系统成功鉴定了一种基于抑制病毒核蛋白-核输出信号3（NP-NES 3）结构域的核输出功能的抗流感化合物DP 2392-E10。在这里，我们证明了DP 2392-E10通过抑制广泛的甲型流感亚型的复制来发挥其抗病毒作用。在分子机制方面，我们揭示了DP 2392-E10抑制病毒NP和核输出蛋白（NEP）的核输出。更具体地，体外拉下测定揭示了DP 2392-E10直接结合细胞CRM 1，其介导NP和NEP的核输出。计算机模拟对接表明，DP 2392-E10在靠近CRM 1的HEAT 9和HEAT 10结构域的区域结合。总之，这些结果表明，CRM 1介导的流感病毒核输出功能代表了抗病毒药物开发的新的潜在靶点，并且还为靶向该功能的新型抑制剂提供了核心结构。DP 2392-E10可抑制多种甲型流感亚型的复制。DP 2392-E10分别通过NP和NEP的NP-NES 3和NEP-NES 2结构域抑制NP和NEP的核输出。DP 2392-E10被预测在靠近HEAT 9和HEAT 10重复的区域中直接结合CRM 1。
An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. DP2392-E10 inhibits replication of a broad range of influenza A subtypes. DP2392-E10 inhibits nuclear exports of NP and NEP via their NP-NES3 and NEP-NES2 domains, respectively. DP2392-E10 is predicted to directly bind CRM1 in the region near the HEAT9 and HEAT10 repeats.
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DOI：
10.1073/pnas.1215214110
发表时间：
2013-01-15
影响因子：
11.1
作者：
Monecke, Thomas;Haselbach, David;Ficner, Ralf
通讯作者：
Ficner, Ralf
影响因子：
64.5
作者：
Fornerod, M;Ohno, M;Mattaj, IW
通讯作者：
Mattaj, IW
影响因子：
5.4
作者：
Perwitasari, Olivia;Johnson, Scott;Tripp, Ralph A.
通讯作者：
Tripp, Ralph A.
影响因子：
3.7
作者：
Cerutti A;Maillard P;Minisini R;Vidalain PO;Roohvand F;Pecheur EI;Pirisi M;Budkowska A
通讯作者：
Budkowska A
甲型流感病毒 NS2 蛋白中第二个 CRM1 依赖性核输出信号有助于病毒核糖核蛋白的核输出
影响因子：
5.4
作者：
Huang, Shengping;Chen, Jingjing;Chen, Ze
通讯作者：
Chen, Ze