unceellolide B，乙型肝炎病毒的新型抑制剂

StephenW

Junceellolide B, a novel inhibitor of Hepatitis B virus
Xiaodan Li  1 , Hui Liu  2 , Wei Cheng  1 , Jie Wang  2 , He Zhang  1 , Fengmin Lu  3 , Xiangmei Chen  4 , Wenhan Lin  5
Affiliations
Affiliations

    1
    State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
    2
    Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China.
    3
    State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China.
    4
    Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China. Electronic address: [email protected].
    5
    State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Institute of Ocean Research, Peking University, Beijing 100875, PR China. Electronic address: [email protected].

    PMID: 32690259 DOI: 10.1016/j.bmc.2020.115603

Abstract

HBV infection is a common cause of liver disease with a high burden worldwide. Current therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure. In this study, a structure-based screening of marine natural products from an in-house library was performed to hit HBV inhibitors, and the gorgonian-derived briarane-type diterpenoids showed inhibitory effects against HBV DNA replication in HepAD38 cells. Preliminary analyses of structure-activity relationship demonstrated that a briarane-based scaffold with an 3E,5(16)-diene and a chlorine-substitution at C-6 is required for the anti-HBV activity. Junceellolide B is one of the potent HBV inhibitors exhibiting efficient reduction of HBsAg and HBeAg production in HBV infected HepG2-NTCP cells with a dose-dependent manner (p < 0.001). It also significantly reduced the secreted HBV DNA, HBV RNA, and HBeAg in HepAD38 cells with the EC50 values of 0.83, 2.87 and 7.75 μM, respectively. Mechanistically, junceellolide B potently inhibited HBV RNA transcription without promoting HBV RNA degradation. RNA-seq analysis indicated that junceellolide B significantly decreased HBV cccDNA-transcripted products accompanying stable down-regulation of the expression of RNA polymerase II related host transcription factors (ZBED6 and ZBTB7B). These findings suggest junceellolide B to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.

Keywords: Briarane-type diterpenoids; Hepatitis B virus; Junceellolide B; Marine natural products; cccDNA.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

StephenW

Junceellolide B，乙型肝炎病毒的新型抑制剂
李晓丹1，刘慧2，魏成1，王杰2，何张1，丰民路3，陈香梅4，林文翰5
隶属关系
隶属关系

    1个
    北京大学天然与仿生药物国家重点实验室，北京100191
    2
    北京大学基础医学院微生物与传染病中心，北京100191
    3
    北京大学天然与仿生药物国家重点实验室，北京100191；北京大学基础医学院微生物与传染病中心，北京100191
    4
    北京大学基础医学院微生物与传染病中心，北京100191电子地址：[email protected]。
    5
    北京大学天然与仿生药物国家重点实验室，北京100191；北京大学海洋研究所，北京100875电子地址：[email protected]。

    PMID：32690259 DOI：10.1016 / j.bmc.2020.115603

抽象

HBV感染是肝脏疾病的常见病因，在世界范围内负担沉重。当前的治疗策略依赖于干扰素和核苷酸（t）化物型药物，但功能性治疗受到限制。在这项研究中，从内部库中对海洋天然产物进行了基于结构的筛选，以检测出HBV抑制剂，而源自戈尔哥尼亚人的briarane型二萜类化合物显示出对HepAD38细胞中HBV DNA复制的抑制作用。初步的结构活性关系分析表明，抗-HBV活性需要具有3E，5（16）-二烯和C-6处氯取代基的基于芳烃的支架。芥子醇内酯B是有效的HBV抑制剂之一，在HBV感染的HepG2-NTCP细胞中表现出有效降低HBsAg和HBeAg产生的剂量依赖性（p <0.001）。它还显着降低了HepAD38细胞中分泌的HBV DNA，HBV RNA和HBeAg，EC50值分别为0.83、2.87和7.75μM。从机理上讲，芥子内酯B有效地抑制了HBV RNA的转录而没有促进HBV RNA的降解。 RNA-seq分析表明，芥菜内酯B显着降低了HBV cccDNA转录产物，并伴随着RNA聚合酶II相关宿主转录因子（ZBED6和ZBTB7B）表达的稳定下调。这些发现表明，芥子素内酯B是cccDNA的转录抑制剂，是开发新型抗HBV药物的有希望的先导。

关键字：芳烃型二萜；乙型肝炎病毒;杜鹃花B;海洋天然产物； cccDNA。

版权所有©2020作者。由Elsevier Ltd.发布。保留所有权利。

StephenW

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