The tyrosine kinase Yes1 is a druggable host factor of HEV.

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2024-10-17 eCollection Date: 2024-11-01 DOI:10.1097/HC9.0000000000000553
Jil Alexandra Haase, Abarna Baheerathan, Xin Zhang, Rebecca Menhua Fu, Maximilian Klaus Nocke, Charlotte Decker, Viet Loan Dao Thi, Daniel Todt, Johan Neyts, Suzanne J F Kaptein, Eike Steinmann, Volker Kinast
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引用次数: 0

Abstract

Background: HEV is a positive-sense, single-stranded RNA virus of the Hepeviridae family. Although HEV accounts for more than 3 million symptomatic cases of viral hepatitis per year, specific anti-HEV therapy and knowledge about HEV pathogenesis are scarce.

Methods: To gain a deeper understanding of the HEV infectious cycle and guide the development of novel antiviral strategies, we here used an RNAi mini screen targeting a selection of kinases, including mitogen-activated protein kinases, receptor tyrosine kinases, and Src-family kinases. Further, we used state-of-the-art HEV infection models, including primary human hepatocytes and athymic nude rats.

Results: Upon knockdown of the Src-family kinase Yes1, a significant reduction of HEV susceptibility could be observed, suggesting an important role of Yes1 in the HEV infectious cycle. Selective inhibition of Yes1 kinase activity resulted in significant inhibition of HEV infection in hepatoma cells and primary human hepatocytes, as well as in a rat HEV in vivo model system. Subsequent analysis of Y1KI during the HEV infectious life cycle indicated a role of Yes1 kinase activity in the early onset of HEV infection.

Conclusions: We identified the dependence of HEV on Yes1 signaling, which may contribute to the so far scarce knowledge of HEV's pathogenesis in the future. Moreover, we provide Y1KI as a novel antiviral drug candidate specifically targeting an HEV host factor.

酪氨酸激酶 Yes1 是 HEV 的可药用宿主因子。
背景:HEV 是肝病毒科的一种正义单链 RNA 病毒。尽管 HEV 每年导致超过 300 万例无症状病毒性肝炎病例,但特异性抗 HEV 治疗和有关 HEV 发病机制的知识却非常匮乏:为了更深入地了解 HEV 的感染周期并指导新型抗病毒策略的开发,我们在这里使用了 RNAi mini 筛选技术,靶向一系列激酶,包括丝裂原活化蛋白激酶、受体酪氨酸激酶和 Src 家族激酶。此外,我们还使用了最先进的 HEV 感染模型,包括原代人类肝细胞和无胸腺裸鼠:结果:在敲除 Src 家族激酶 Yes1 后,可以观察到 HEV 易感性显著降低,这表明 Yes1 在 HEV 感染循环中发挥着重要作用。选择性抑制 Yes1 激酶活性可显著抑制肝癌细胞和原代人类肝细胞以及大鼠 HEV 体内模型系统中的 HEV 感染。随后对 HEV 感染生命周期中 Y1KI 的分析表明,Yes1 激酶的活性在 HEV 感染的早期起始阶段发挥作用:结论:我们发现了 HEV 对 Yes1 信号转导的依赖性,这可能有助于今后对迄今为止尚缺乏的 HEV 发病机制的了解。此外,我们还提供了专门针对 HEV 宿主因子的新型抗病毒候选药物 Y1KI。
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
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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