Asiatic acid inhibits HBV cccDNA transcription by promoting HBx degradation.

IF 4 3区医学 Q2 VIROLOGY

Virology Journal Pub Date : 2024-10-28 DOI:10.1186/s12985-024-02535-3

Ranran Li, Chunduo Wang, Kexin Xu, Zongzhu Zhan, Siyi He, Jihua Ren, Fan Li, Nana Tao, Zhihong Li, Zhen Yang, Haibo Yu

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引用次数: 0

Abstract

Background: Hepatitis B virus (HBV) infection is a persistent global public health problem, and curing for chronic hepatitis B (CHB) through the application of existing antiviral drugs is beset by numerous challenges. The viral protein HBx is a critical regulatory factor in the life cycle of HBV. Targeting HBx is a promising possibility for the development of novel therapeutic strategies.

Methods: The Nano-Glo^® HiBiT Lysis Detection System was used to screen the herbal monomer compound library for compounds that inhibit HBx expression. Western blotting was used to examine proteins expression. Southern blotting or Northern blotting were used to detect HBV DNA or HBV RNA. ELISA was performed to detect the HBsAg level. The effect of asiatic acid on HBV in vivo was investigated by using recombinant cccDNA mouse model.

Results: Asiatic acid, an extract of Centella asiatica, significantly reduced the HBx level. Mechanistic studies demonstrated that asiatic acid may promote the degradation of HBx in an autophagy pathway-dependent manner. Subsequently, asiatic acid was found to reduce the amount of HBx bound to covalently closed circular DNA (cccDNA) microchromosomes, and repressive chromatin modifications then occurred, ultimately inhibiting cccDNA transcriptional activity. Moreover, in HBV-infected cells and a mouse model of persistent HBV infection, asiatic acid exhibited potent anti-HBV activity, as evidenced by decreased levels of HBV RNAs, HBV DNA and HBsAg.

Conclusions: Asiatic acid was identified as a compound that targets HBx, revealing its potential for application as an anti-HBV agent.

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积雪草酸通过促进 HBx 降解抑制 HBV cccDNA 转录。

背景：乙型肝炎病毒（HBV）感染是一个长期存在的全球性公共卫生问题，通过应用现有的抗病毒药物治愈慢性乙型肝炎（CHB）面临诸多挑战。病毒蛋白 HBx 是 HBV 生命周期中的关键调节因子。以 HBx 为靶点有望开发出新型治疗策略：方法：使用 Nano-Glo® HiBiT 裂解检测系统筛选草药单体化合物库中抑制 HBx 表达的化合物。用 Western 印迹法检测蛋白质的表达。Southern 印迹法或 Northern 印迹法用于检测 HBV DNA 或 HBV RNA。用 ELISA 检测 HBsAg 水平。利用重组cccDNA小鼠模型研究了积雪草酸对体内HBV的影响：结果：积雪草提取物积雪草酸能显著降低 HBx 水平。机理研究表明，积雪草酸可通过自噬途径促进 HBx 的降解。随后，研究发现积雪草酸能减少与共价闭环 DNA（cccDNA）微染色质结合的 HBx 数量，进而发生抑制性染色质修饰，最终抑制cccDNA 的转录活性。此外，在 HBV 感染细胞和小鼠持续 HBV 感染模型中，积雪草酸表现出了强效的抗 HBV 活性，这体现在 HBV RNA、HBV DNA 和 HBsAg 水平的降低上：结论：积雪草酸是一种靶向 HBx 的化合物，揭示了其作为抗 HBV 药物的应用潜力。

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

Virology Journal 医学-病毒学

CiteScore

7.40

自引率

2.10%

发文量

186

审稿时长

1 months

期刊介绍： Virology Journal is an open access, peer reviewed journal that considers articles on all aspects of virology, including research on the viruses of animals, plants and microbes. The journal welcomes basic research as well as pre-clinical and clinical studies of novel diagnostic tools, vaccines and anti-viral therapies. The Editorial policy of Virology Journal is to publish all research which is assessed by peer reviewers to be a coherent and sound addition to the scientific literature, and puts less emphasis on interest levels or perceived impact.