1. Academic Validation
  2. 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

  • Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00608-20. doi: 10.1128/AAC.00608-20.
Li-Feng Chen 1 Wei-Bin Xu 1 Yue-Yue Li 1 Neng-Hua Chen 1 Ding Luo 1 Qiao-Yun Song 1 Wei Tang 1 Zhi-Gang Huang 2 Yao-Lan Li 3 Zhong Liu 4 Man-Mei Li 3
Affiliations

Affiliations

  • 1 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
  • 2 Qianwan Pharmaceutical Technology Company Limited, Shenzhen, Guangdong, China.
  • 3 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China [email protected] [email protected] [email protected].
  • 4 Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China [email protected] [email protected] [email protected].
Abstract

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.

Keywords

PI3K signaling; PIK-24; RSV entry; actin cytoskeleton rearrangement; anti-RSV activity; fusion process.

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