PLX8394, a RAF inhibitor, inhibits enterovirus 71 replication by blocking RAF/MEK/ERK signaling

Chengyuan Wu; Guangyan Zhu; Fang Qiu; Fuli Ren; Binbin Lin; Dingyu Zhang; Qingyu Yang; Chaolin Huang

doi:10.1016/j.virs.2023.01.006

April 2023

. doi: 10.1016/j.virs.2023.01.006

Citation: Chengyuan Wu, Guangyan Zhu, Fang Qiu, Fuli Ren, Binbin Lin, Dingyu Zhang, Qingyu Yang, Chaolin Huang. PLX8394, a RAF inhibitor, inhibits enterovirus 71 replication by blocking RAF/MEK/ERK signaling .VIROLOGICA SINICA, 2023, 38(2) : 276-284. http://dx.doi.org/10.1016/j.virs.2023.01.006

PLX8394,一种RAF抑制剂，通过阻断RAF/MEK/ERK信号通路抑制肠病毒71复制

吴成园 ^a ,
祝光燕 ^a ,
邱芳 ^a ,
任富利 ^a,b ,
林彬彬 ^a,c ,
张定宇 ^a,, ,
杨庆雨 ^a,, ,
黄朝林 ^a,,

a. 华中科技大学同济医学院附属武汉金银潭医院;
b. 中国科学院武汉病毒研究所病毒学国家重点实验室;
c. 中国科学技术大学生命科学与医学部

通讯作者： 张定宇, 2020jy0001@hust.edu.cn; 杨庆雨, yangqingyu8671@163.com; 黄朝林, 2020jy0003@hust.edu.cn
收稿日期： 2022-10-10
录用日期： 2023-01-13

摘要

肠病毒71型（EV71）长期在世界各地零星暴发与流行，仍然对人类健康构成严重威胁。目前仅有几种针对EV71部分亚型的疫苗，但没有特效治疗EV71感染的药物。因此，开发抗EV71病毒的药物是迫切需要的。在这里，我们发现一种RAF抑制剂——PLX8394，在体外对EV71具有较高的抗病毒活性，优于传统的临床药物利巴韦林。此外，PLX8394对肠道病毒表现出广谱抗病毒活性。更值得注意的是，在乳鼠模型中，PLX8394对EV71感染小鼠的保护率达到70%，降低了肝脏和心脏组织中的病毒载量，缓解脏器的炎症反应。相关机制研究表明，PLX8394是通过抑制RAF/MEK/ERK信号通路抑制EV71复制。因此，PLX8394抗病毒作用的发现为开发抗EV71新药奠定了基础。
- 肠病毒71型(EV71)
- , RAF抑制剂
- , 手足口病
- , RAF/MEK/ERK信号通路
- , 抗病毒药物

PLX8394, a RAF inhibitor, inhibits enterovirus 71 replication by blocking RAF/MEK/ERK signaling

Chengyuan Wu ^a ,
Guangyan Zhu ^a ,
Fang Qiu ^a ,
Fuli Ren ^a,b ,
Binbin Lin ^a,c ,
Dingyu Zhang ^a,, ,
Qingyu Yang ^a,, ,
Chaolin Huang ^a,,

a. Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, China;
b. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China;
c. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China

Corresponding author: Dingyu Zhang, 2020jy0001@hust.edu.cn Qingyu Yang, yangqingyu8671@163.com Chaolin Huang, 2020jy0003@hust.edu.cn
Received Date: 10 October 2022
Accepted Date: 13 January 2023

Abstract

Enterovirus 71 (EV71) poses a serious threat to human health, with scattered outbreaks worldwide. There are several vaccines against a few EV71 strains but no efficient drug for the treatment of EV71 infection. Therefore, it is urgent and of significance to develop anti-EV71 drugs. Here, we found that PLX8394, a RAF inhibitor, possesses high antiviral activity against EV71 in vitro, being superior to the traditional clinical drug ribavirin. Moreover, PLX8394 exhibits broad-spectrum antiviral activity against enteroviruses. Notably, in a suckling mouse model, PLX8394 provided a 70% protection rate for EV71-infected mice, reduced the viral load in liver and heart tissues, and relieved the inflammatory response. A mechanistic study showed that PLX8394 inhibited EV71 by suppressing the RAF/MEK/ERK signaling pathway. Thus, PLX8394 lays a foundation for the development of new drugs against EV71.
- Enterovirus 71 (EV71)
- , RAF inhibitor
- , Hand, foot, and mouth disease (HFMD)
- , RAF/MEK/ERK signaling Pathway
- , Antiviral agents

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