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

IF 5.5 3区医学 Q1 Medicine

Virologica Sinica Pub Date : 2025-06-01 DOI:10.1016/j.virs.2025.05.009

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

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引用次数: 0

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.

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Eltrombopag是一种fda批准的药物，通过靶向NS2B-NS3蛋白酶抑制登革热病毒2型。

登革热病毒（DENV）已在全球蔓延，对人类生命构成巨大威胁。最广泛的血清型是2型登革热病毒（DENV 2），没有特异性治疗方法。NS2B-NS3蛋白酶在DENV复制中起关键作用，因为它具有切割病毒多蛋白的功能；因此，它被认为是发现抗病毒药物的一个有希望的靶点。在这项研究中，我们开发了一个基于NS2B-NS3蛋白酶的高通量筛选系统，从fda批准的药物库中识别候选药物。Eltrombopag从3273种药物中筛选出来，在体外显示出微摩尔水平的DENV 2抑制作用，在腹腔注射后显著降低了攻击小鼠靶器官中的病毒载量。进一步的机制分析表明，eltrombopag以可逆、非竞争性的方式与DENV - 2 NS2B-NS3蛋白酶变变结合，从而在感染后阶段抑制DENV - 2。此外，eltrombopag抑制DENV 4和寨卡病毒的NS2B-NS3蛋白酶，提示其作为广谱抗病毒药物的潜力。本研究重新定位了eltrombopag作为一种有前景的DENV抗病毒药物，为黄病毒抗病毒药物的开发提供了另一种选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Virologica Sinica Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

7.70

自引率

1.80%

发文量

3149

期刊介绍： Virologica Sinica is an international journal which aims at presenting the cutting-edge research on viruses all over the world. The journal publishes peer-reviewed original research articles, reviews, and letters to the editor, to encompass the latest developments in all branches of virology, including research on animal, plant and microbe viruses. The journal welcomes articles on virus discovery and characterization, viral epidemiology, viral pathogenesis, virus-host interaction, vaccine development, antiviral agents and therapies, and virus related bio-techniques. Virologica Sinica, the official journal of Chinese Society for Microbiology, will serve as a platform for the communication and exchange of academic information and ideas in an international context. Electronic ISSN: 1995-820X; Print ISSN: 1674-0769