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

作者：Xuerui Zhu, Xiao Gao, Wu Yan, Jia Lu, Xinlan Chen, Chenshu Zhao, Haoyu Li, Zhongfa Zhang, Shuwen Liu, Gengfu Xiao, Xiaoyan Pan · 发表于：Virologica Sinica · 年份：2025 · DOI：10.1016/j.virs.2025.05.009 · 被引用次数：9 · 研究领域：Mosquito-borne diseases and control、Viral Infections and Vectors、Malaria Research and Control

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.