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
  • 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: [email protected].
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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