. doi: 10.1016/j.virs.2024.02.006
Citation: Qiu-Yan Zhang, Jia-Qi Li, Qi Li, Yang Zhang, Zhe-Rui Zhang, Xiao-Dan Li, Hong-Qing Zhang, Cheng-Lin Deng, Feng-Xia Yang, Yi Xu, Bo Zhang. Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening .VIROLOGICA SINICA, 2024, 39(2) : 301-308.  http://dx.doi.org/10.1016/j.virs.2024.02.006

基于报告病毒的高内涵抗病毒药物筛选系统明确防己诺林碱可作为广谱的抗肠道病毒抑制剂

  • 手足口病(HFMD)是一种常见的儿科疾病,主要由肠道病毒引起,肠道病毒是重要的人类病原体。目前,还没有可用的抗病毒药物治疗肠道病毒感染。本研究利用EV-A71-eGFP报告病毒开发了一种优良的高内涵抗病毒筛选系统。基于该系统,我们筛选了包含1042种天然化合物的药物库,以鉴定潜在的EV-A71抑制剂。防己诺林碱(FAN)是一种双苄基异喹啉类生物碱,对引起手足口病的EV-A71、CV-A10、CV-B3和CV-A16等多种肠道病毒具有抑制作用。进一步的研究表明,FAN靶向肠道病毒生命周期的早期阶段。通过进一步筛选抗FAN的EV-A71耐药病毒株,我们证明VP1的两个突变(E145G和V258I)可使病毒对FAN产生抗性,推测VP1蛋白可能是FAN的潜在靶点。我们的研究表明,FAN是一种有效的EV-A71抑制剂,具有进一步成为一种广谱抗肠道病毒药物的潜力。

Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening

  • Hand, foot, and mouth disease (HFMD) is a common pediatric illness mainly caused by enteroviruses, which are important human pathogens. Currently, there are no available antiviral agents for the therapy of enterovirus infection. In this study, an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed. Using this screening system, we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, exhibits potential inhibitory effects against various enteroviruses that cause HFMD, such as EV-A71, CV-A10, CV-B3 and CV-A16. Further investigations revealed that FAN targets the early stage of the enterovirus life cycle. Through the selection of FAN-resistant EV-A71 viruses, we demonstrated that the VP1 protein could be a potential target of FAN, as two mutations in VP1 (E145G and V258I) resulted in viral resistance to FAN. Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

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    Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening

      Corresponding author: Yi Xu, xuyi70@163.com
      Corresponding author: Bo Zhang, zhangbo@wh.iov.cn
    • a. The Joint Center of Translational Precision Medicine, Department of Infections and Diseases, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, 510623, China;
    • b. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
    • c. University of Science and Technology of China, Department of Life Sciences and Medicine, Hefei, 230026, China;
    • d. Hunan Normal University, School of Medicine, Changsha, 410081, China

    Abstract: Hand, foot, and mouth disease (HFMD) is a common pediatric illness mainly caused by enteroviruses, which are important human pathogens. Currently, there are no available antiviral agents for the therapy of enterovirus infection. In this study, an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed. Using this screening system, we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, exhibits potential inhibitory effects against various enteroviruses that cause HFMD, such as EV-A71, CV-A10, CV-B3 and CV-A16. Further investigations revealed that FAN targets the early stage of the enterovirus life cycle. Through the selection of FAN-resistant EV-A71 viruses, we demonstrated that the VP1 protein could be a potential target of FAN, as two mutations in VP1 (E145G and V258I) resulted in viral resistance to FAN. Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

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