Inhibitory Effect of PIK-24 on Respiratory Syncytial Virus Entry by Blocking Phosphatidylinositol-3 Kinase Signaling
Inhibitory Effect of PIK-24 on Respiratory Syncytial Virus Entry by Blocking Phosphatidylinositol-3 Kinase Signaling
复制标题
DOI：
10.1128/aac.00608-20
复制
发表时间：
2020-10-01
影响因子：
4.9
通讯作者：
Li, Man-Mei
中科院分区：
文献类型：
--
作者：
Chen, Li-Feng;Xu, Wei-Bin;Li, Man-Mei
Phosphoinositide-3 激酶信号传导调节许多细胞过程，包括细胞存活、增殖、分化和凋亡。目前，已知呼吸道合胞病毒感染的建立需要磷酸肌醇-3激酶信号传导。然而，呼吸道合胞病毒进入呼吸道合胞病毒过程中磷酸肌醇3激酶信号传导的调控模式或其相应的分子机制仍不清楚。在此，研究了磷酸肌醇 3 激酶信号传导在呼吸道合胞病毒进入中的参与。 PIK-24 是一种以磷酸肌醇 3 激酶为靶点设计的新型化合物，在体外和体内均具有有效的抗呼吸道合胞病毒活性。 PIK-24 通过阻断融合过程的后期，显着减少病毒进入宿主细胞。在小鼠模型中，PIK-24 有效降低病毒载量并减轻肺组织炎症。随后对 PIK-24 抗病毒机制的研究表明，病毒进入时伴随着磷酸肌醇 3 激酶信号激活、下游 RhoA 和丝切蛋白上调以及肌动蛋白细胞骨架重排。 PIK-24 治疗显着逆转了所有这些影响。通过敲低破坏肌动蛋白细胞骨架动力学或调节磷酸肌醇 3 激酶活性也影响病毒进入功效。总而言之，可以合理地得出以下结论：PIK-24 的抗病毒活性取决于磷酸肌醇 3 激酶信号传导，并且使用磷酸肌醇 3 激酶信号传导调节肌动蛋白细胞骨架重排在呼吸道合胞病毒进入中发挥关键作用。
Phosphoinositide-3 kinase signaling modulates many cellular processes, including cell survival, proliferation, differentiation, and apoptosis. Currently, it is known that the establishment of respiratory syncytial virus infection requires phosphoinositide-3 kinase signaling. However, the regulatory pattern of phosphoinositide-3 kinase signaling or its corresponding molecular mechanism during respiratory syncytial virus entry remains unclear. Here, the involvement of phosphoinositide-3 kinase signaling in respiratory syncytial virus entry was studied. PIK-24, a novel compound designed with phosphoinositide-3 kinase as a target, had potent anti-respiratory syncytial virus activity both in vitro and in vivo. PIK-24 significantly reduced viral entry into the host cell through blocking the late stage of the fusion process. In a mouse model, PIK-24 effectively reduced the viral load and alleviated inflammation in lung tissue. Subsequent studies on the antiviral mechanism of PIK-24 revealed that viral entry was accompanied by phosphoinositide-3 kinase signaling activation, downstream RhoA and cofilin upregulation, and actin cytoskeleton rearrangement. PIK-24 treatment significantly reversed all these effects. The disruption of actin cytoskeleton dynamics or the modulation of phosphoinositide-3 kinase activity by knockdown also affected viral entry efficacy. Altogether, it is reasonable to conclude that the antiviral activity of PIK-24 depends on the phosphoinositide-3 kinase signaling and that the use of phosphoinositide-3 kinase signaling to regulate actin cytoskeleton rearrangement plays a key role in respiratory syncytial virus entry.