过氧化麦角甾醇通过抑制 LHBsAg 的前 S1 结构域与 NTCP 的结合

StephenW

过氧化麦角甾醇通过抑制 LHBsAg 的前 S1 结构域与 NTCP 的结合来抑制 HBV 感染
黄兴 1 , 黄秀珍 2 , 邱伟中 1 , 林烈泉 3 , 陈瑞杰 4 , 刘慧康 5 , 赖玉恒 6 , 黄诚 7
隶属关系
隶属关系

    1
    台湾台北国立阳明交通大学医学生物技术与实验室科学系。
    2
    台湾新竹国立清华大学南校区应用科学系；台湾新竹国立清华大学教师教育中心。
    3
    台湾台北市卫生福利部国立中医药研究所。
    4
    台湾嘉义国立嘉义大学生化科学与技术系。
    5
    台湾台北市卫生福利部国立中医药研究所；台湾台北市台北医科大学草药临床药物开发博士项目。
    6
    中国文化大学化学系，台北，台湾。
    7
    台湾台北国立阳明交通大学医学生物技术与实验室科学系。电子地址：[email protected]。

    PMID：34627935 DOI：10.1016/j.antiviral.2021.105184

抽象的

乙型肝炎病毒 (HBV) 感染会导致严重的肝脏疾病，包括肝硬化和肝细胞癌 (HCC)。超过 2.57 亿人被慢性感染，特别是在西太平洋区域和非洲。尽管核苷酸和核苷类似物 (NUC) 和干扰素 (IFN) 是 HBV 感染的标准疗法，但没有一种能从受感染的肝细胞中根除 HBV 共价闭合环状 DNA (cccDNA)。此外，NUC 的长期治疗会增加产生耐药性的风险，而 IFN 可能会对患者造成严重的副作用。因此，非常需要一种能够实现功能性治愈甚至完全消除病毒的新型 HBV 疗法。关于 HBV 生命周期，靶向 HBV 感染进入步骤的药物会抢先减少肝内 cccDNA 库。 HBV 感染的初始进入步骤涉及乙型肝炎大表面蛋白 (LHBsAg) 的前 S1 结构域与牛磺胆酸钠协同转运多肽 (NTCP) 之间的相互作用，NTCP 是 HBV 的受体。在这项研究中，过氧化麦角甾醇 (EP) 被确定为 HBV 进入的新抑制剂。 EP 抑制 HBV 进入 DMSO 分化的永生化原代人肝细胞 HuS-E/2 细胞的早期步骤，这些细胞过表达 NTCP。此外，EP 通过作用于 NTCP 直接干扰 NTCP-LHBsAg 相互作用。此外，EP 对 HBV 基因组复制、病毒体完整性或病毒体分泌没有影响。最后，EP 对 HBV 基因型 A-D 感染的活性突出了 EP 对抗 HBV 感染的治疗潜力。

关键词：进入抑制剂；过氧化麦角甾醇;乙肝表面抗原；乙型肝炎病毒; NTCP。

版权所有 © 2021。Elsevier B.V. 出版

StephenW

Ergosterol peroxide inhibits HBV infection by inhibiting the binding of the pre-S1 domain of LHBsAg to NTCP
Hsing Huang  1 , Hsiu-Chen Huang  2 , Wei-Chung Chiou  1 , Lie-Chwen Lin  3 , Jui-Chieh Chen  4 , Hui-Kang Liu  5 , Yu-Heng Lai  6 , Cheng Huang  7
Affiliations
Affiliations

    1
    Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
    2
    Department of Applied Science, National Tsing Hua University South Campus, Hsinchu, Taiwan; Center for Teacher Education, National Tsing Hua University, Hsinchu, Taiwan.
    3
    National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
    4
    Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
    5
    National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Ph. D. Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan.
    6
    Department of Chemistry, Chinese Culture University, Taipei, Taiwan.
    7
    Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address: [email protected].

    PMID: 34627935 DOI: 10.1016/j.antiviral.2021.105184

Abstract

Hepatitis B virus (HBV) infection leads to severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). More than 257 million individuals are chronically infected, particularly in the Western Pacific region and Africa. Although nucleotide and nucleoside analogues (NUCs) and interferons (IFNs) are the standard therapeutics for HBV infection, none eradicates HBV covalently closed circular DNA (cccDNA) from the infected hepatocytes. In addition, long-term treatment with NUCs increases the risk of developing drug resistance and IFNs may cause severe side effects in patients. Thus, a novel HBV therapy that can achieve a functional cure, or even complete elimination of the virus, is highly desirable. Regarding the HBV life cycle, agents targeting the entry step of HBV infection reduce the intrahepatic cccDNA pool preemptively. The initial entry step in HBV infection involves interaction between the pre-S1 domain of the large hepatitis B surface protein (LHBsAg) and the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. In this study, ergosterol peroxide (EP) was identified as a new inhibitor of HBV entry. EP inhibits an early step of HBV entry into DMSO-differentiated immortalized primary human hepatocytes HuS-E/2 cells, which were overexpressed NTCP. Also, EP interfered directly with the NTCP-LHBsAg interaction by acting on the NTCP. In addition, EP had no effect on HBV genome replication, virion integrity or virion secretion. Finally, the activity of EP against infection with HBV genotypes A-D highlights the therapeutic potential of EP for fighting HBV infection.

Keywords: Entry inhibitor; Ergosterol peroxide; HBsAg; Hepatitis B virus; NTCP.

Copyright © 2021. Published by Elsevier B.V.