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

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

  • Virol Sin. 2025 Jun;40(3):439-450. doi: 10.1016/j.virs.2025.05.009.
Xuerui Zhu 1,  Xiao Gao 2,  Yan Wu 1,  Jia Lu 2,  Xinlan Chen 2,  Chenshu Zhao 1,  Haoyu Li 2,  Zhongfa Zhang 1,  Shuwen Liu 3,  Gengfu Xiao 2,  Xiaoyan Pan 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430207, China.
  • 2 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430207, China; University of Chinese Academy of Sciences, Beijing 101400, China.
  • 3 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 4 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430207, China; University of Chinese Academy of Sciences, Beijing 101400, China. Electronic address: panxy@wh.iov.cn.
PMID: 40447137 DOI: 10.1016/j.virs.2025.05.009
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.

Keywords

Allosteric inhibitor; Antiviral agent; Dengue virus type 2 (DENV 2); Eltrombopag; NS2B-NS3 protease.

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