PDF(Pubmed)
Abstract：
Nuclear export of the viral ribonucleoprotein (vRNP) is a critical step in the influenza A virus (IAV) life cycle and may be an effective target for the development of anti-IAV drugs. The host factor ras-related nuclear protein (RAN) is known to participate in the life cycle of several viruses, but its role in influenza virus replication remains unknown. In the present study, we aimed to determine the function of RAN in influenza virus replication using different cell lines and subtype strains. We found that RAN is essential for the nuclear export of vRNP, as it enhances the binding affinity of XPO1 toward the viral nuclear export protein NS2. Depletion of RAN constrained the vRNP complex in the nucleus and attenuated the replication of various subtypes of influenza virus. Using in silico compound screening, we identified that bepotastine could dissociate the RAN-XPO1-vRNP trimeric complex and exhibit potent antiviral activity against influenza virus both in vitro and in vivo. This study demonstrates the important role of RAN in IAV replication and suggests its potential use as an antiviral target.
摘要：
病毒核糖核蛋白（vRNP）的核输出是甲型流感病毒（IAV）生命周期中的关键步骤，可能是开发抗IAV药物的有效靶标。已知宿主因子ras相关核蛋白（RAN）参与几种病毒的生命周期，但其在流感病毒复制中的作用尚不清楚。在本研究中,我们的目的是使用不同的细胞系和亚型毒株确定RAN在流感病毒复制中的功能。我们发现RAN对于vRNP的核出口至关重要，因为它增强了XPO1对病毒核输出蛋白NS2的结合亲和力。RAN的耗尽限制了细胞核中的vRNP复合物并减弱了各种亚型流感病毒的复制。使用硅化合物筛选，我们确定bepotastine可以解离RAN-XPO1-vRNP三聚体复合物，并在体外和体内表现出对流感病毒的有效抗病毒活性。这项研究证明了RAN在IAV复制中的重要作用，并表明其作为抗病毒剂的潜在用途。
