Eltrombopag, an FDA-approved drug, inhibits dengue virus type 2 by targeting NS2B-NS3 protease

Xuerui Zhu; Xiao Gao; Yan Wu; Jia Lu; Xinlan Chen; Chenshu Zhao; Haoyu Li; Zhongfa Zhang; Shuwen Liu; Gengfu Xiao; Xiaoyan Pan

doi:10.1016/j.virs.2025.05.009

June 2025

. doi: 10.1016/j.virs.2025.05.009

Citation: Xuerui Zhu, Xiao Gao, Yan Wu, Jia Lu, Xinlan Chen, Chenshu Zhao, Haoyu Li, Zhongfa Zhang, Shuwen Liu, Gengfu Xiao, Xiaoyan Pan. Eltrombopag, an FDA-approved drug, inhibits dengue virus type 2 by targeting NS2B-NS3 protease .VIROLOGICA SINICA, 2025, 40(3) : 439-450. http://dx.doi.org/10.1016/j.virs.2025.05.009

Eltrombopag通过抑制NS2B-NS3丝氨酸蛋白酶活性发挥抗登革病毒作用

朱雪锐 ^a ,
高晓 ^a,b ,
吴妍 ^a ,
陆嘉 ^a,b ,
陈欣澜 ^a,b ,
赵晨姝 ^a ,
李昊昱 ^a,b ,
张中发 ^a ,
刘叔文 ^c ,
肖庚富 ^a,b ,
潘晓彦 ^a,b,,

a 中国科学院武汉病毒研究所, 高致病性病毒与生物安全全国重点实验室, 武汉 430207;
b 中国科学院大学, 北京 101400;
c 南方医科大学, 药学院, 广州 510515

通讯作者： 潘晓彦, panxy@wh.iov.cn
收稿日期： 2025-02-19
录用日期： 2025-05-26

摘要

蚊媒病毒登革病毒（DENV），尤其是2型DENV（DENV 2），在东南亚和太平洋岛屿等热带、亚热带区域持续流行，但无特异治疗药物，对人类生命健康构成较大威胁。DENV NS2B-NS3 丝氨酸蛋白酶在病毒复制过程中发挥切割病毒多聚蛋白的功能，因此被作为有希望的抗病毒靶标进行药物开发。本研究旨在基于 NS2B-NS3pro 建立高通量体外筛选系统，并从 FDA 批准的药物库中鉴定候选药物。Eltrombopag被从3273种药物中筛选出来，它在体外对DENV 2的抑制作用达微摩尔水平，腹腔给药后可显著降低攻毒小鼠靶器官中的病毒载量。理论分析结合试验表明，eltrombopag通过可逆、非竞争的方式与NS2B-NS3pro产生变构结合，从而在感染后阶段发挥抗DENV 2作用。此外，eltrombopag 对DENV 4 和寨卡病毒（ZIKV）的 NS2B-NS3pro也具有抑制作用，提示其广谱抗黄病毒的可能。该研究重定位了FDA批准的药物，艾曲波帕，在抗 DENV感染方面的应用前景，同时为抗黄病毒的药物开发提供了另一种选择。
- 2 型登革热病毒（DENV 2）
- , 抗病毒药物
- , NS2B-NS3 蛋白酶
- , 艾曲波帕
- , 变构抑制剂

Eltrombopag, an FDA-approved drug, inhibits dengue virus type 2 by targeting NS2B-NS3 protease

Xuerui Zhu ^a ,
Xiao Gao ^a,b ,
Yan Wu ^a ,
Jia Lu ^a,b ,
Xinlan Chen ^a,b ,
Chenshu Zhao ^a ,
Haoyu Li ^a,b ,
Zhongfa Zhang ^a ,
Shuwen Liu ^c ,
Gengfu Xiao ^a,b ,
Xiaoyan Pan ^a,b,,

a. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430207, China;
b. University of Chinese Academy of Sciences, Beijing 101400, China;
c. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China

Corresponding author: Xiaoyan Pan, panxy@wh.iov.cn
Received Date: 19 February 2025
Accepted Date: 26 May 2025

Abstract

Dengue viruses (DENV) have spread throughout the world and pose a huge threat to human life. The most widespread serotype is type 2 DENV (DENV 2), which has no specific treatment. NS2B-NS3 protease plays a pivotal role in DENV replication because of its function in cleavage of the viral polyprotein; thus, it is considered a promising target for antiviral discovery. In this study, we developed a high-throughput screening system based on the NS2B-NS3 protease to identify candidates from an FDA-approved drug library. Eltrombopag was screened out of 3273 drugs, and demonstrated inhibition on DENV 2 at the micromolar level in vitro, significantly reducing viral loads in the targeted organs of challenged mice following intraperitoneal injection. Further mechanistic analysis showed that eltrombopag allosterically binds to the DENV 2 NS2B-NS3 protease in a reversible, non-competitive manner, therefore inhibiting DENV 2 at the post-infection stage. In addition, eltrombopag inhibited the NS2B-NS3 proteases of DENV 4 and Zika virus, suggesting its potential as a broad-spectrum antiviral agent. This study repurposed eltrombopag as a promising antiviral agent against DENV, providing an alternative for antiviral development against flaviviruses.
- Dengue virus type 2 (DENV 2)
- , Antiviral agent
- , NS2B-NS3 protease
- , Eltrombopag
- , Allosteric inhibitor

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