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复方IMB-Z通过增加APOBEC3G表达并掺入病毒核衣壳抑制乙型肝炎 [复制链接]

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才高八斗

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发表于 2022-11-19 12:36 |只看该作者 |倒序浏览 |打印
复方IMB-Z通过增加APOBEC3G表达并掺入病毒核衣壳抑制乙型肝炎病毒复制
胡金 1、王辉强 1、杨路 1、吴硕 2、李艳萍 3、李玉环 4、李卓荣 5
隶属关系
隶属关系

    1个
    中国医学科学院抗病毒药物研究重点实验室,中国医学科学院和北京协和医学院药物生物技术研究所,北京,中国。北京市抗菌药物重点实验室,中国医学科学院和北京协和医学院药物生物技术研究所,北京,中国。中国医学科学院和北京协和医学院药物生物技术研究所国家卫生健康委抗生素生物技术重点实验室,中国北京。
    2个
    中国医学科学院抗病毒药物研究重点实验室,中国医学科学院和北京协和医学院药物生物技术研究所,北京,中国。北京市抗菌药物重点实验室,中国医学科学院和北京协和医学院药物生物技术研究所,北京,中国。中国医学科学院北京协和医学院药物生物技术研究所,国家卫生健康委抗生素生物技术重点实验室,北京,中国。电子地址:[email protected]
    3个
    中国医学科学院抗病毒药物研究重点实验室,中国医学科学院北京协和医学院药物生物技术研究所,北京,中国。电子地址:[email protected]
    4个
    中国医学科学院抗病毒药物研究重点实验室,中国医学科学院和北京协和医学院药物生物技术研究所,北京,中国。北京市抗菌药物重点实验室,中国医学科学院和北京协和医学院药物生物技术研究所,北京,中国。中国医学科学院北京协和医学院药物生物技术研究所,国家卫生健康委抗生素生物技术重点实验室,北京,中国。电子地址:[email protected]
    5个
    中国医学科学院药物生物技术研究所中国医学科学院北京协和医学院抗病毒药物研究重点实验室,中国北京。

    PMID:36396043 DOI:10.1016/j.jgar.2022.11.006

抽象的

背景:作为宿主限制因素,载脂蛋白 B 信使 RNA 编辑酶催化多肽样 3G(APOBEC3G 或 A3G)已被证明可以抑制包括乙型肝炎病毒(HBV)在内的多种病毒的复制。最近,我们报道了 N-苯基苯甲酰胺衍生物 IMB-Z 可以抑制肠道病毒 71 (EV71) 复制,A3G 介导其抗病毒活性。尚未研究 IMB-Z 是否对 HBV 复制具有抑制作用。

材料和方法:HBV DNA、前基因组 RNA (pgRNA)、核心蛋白和衣壳水平分别通过 qPCR 测定或 Southern 印迹、Northern 印迹、Western 印迹和颗粒凝胶测定确定。通过差异 DNA 变性 PCR 测定法检测 HBV DNA 的突变分析。在超速离心和 HBV 核心蛋白和 A3G 蛋白之间的免疫共沉淀 (IP) 测定后,通过蛋白质印迹分析检查 A3G 包壳到 HBV 核衣壳中。

结果:在本研究中,我们发现 IMB-Z 可以显着抑制 HepAD38 细胞中的 HBV 复制。有趣的是,IMB-Z 没有改变 HBV pgRNA 的产生,但可以降低核心蛋白、病毒核衣壳和核心相关 DNA 的水平,以及 cccDNA 细胞内扩增。与 IMB-Z 对 EV71 复制的抑制作用类似,我们发现 IMB-Z 对 HBV 复制的抑制与 A3G 水平升高有关。从机制上讲,我们证明了 IMB-Z 的抑制作用不依赖于 A3G 的胞苷脱氨酶活性,并且通过增加其在病毒核衣壳中的掺入来发挥作用。

结论:我们的结果表明 IMB-Z 通过药理学诱导 A3G 表达和掺入 HBV 核衣壳来抑制 HBV。

关键词:APOBEC3G; IMB-Z;乙型肝炎病毒;公司成立。

版权所有 © 2022。Elsevier Ltd. 出版。

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才高八斗

2
发表于 2022-11-19 12:37 |只看该作者
Compound IMB-Z inhibits hepatitis B virus replication through increasing APOBEC3G expression and incorporation into viral nucleocapsids
Jin Hu  1 , Huiqiang Wang  1 , Lu Yang  1 , Shuo Wu  2 , Yanping Li  3 , Yuhuan Li  4 , Zhuorong Li  5
Affiliations
Affiliations

    1
    CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
    2
    CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.. Electronic address: [email protected].
    3
    CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.. Electronic address: [email protected].
    4
    CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.. Electronic address: [email protected].
    5
    CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    PMID: 36396043 DOI: 10.1016/j.jgar.2022.11.006

Abstract

Background: As a host restriction factor, apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) has been shown to suppress the replication of several viruses including hepatitis B virus (HBV). Recently, we reported that IMB-Z, a N-phenylbenzamide derivative, could inhibit Enterovirus 71 (EV71) replication and A3G mediated its antiviral activity. Whether IMB-Z exhibits an inhibitory effect on HBV replication has not been investigated.

Material and methods: HBV DNA, pregenomic RNA (pgRNA), core protein, and capsid levels were determined by a qPCR assay or Southern blot, Northern blot, Western blot and particle gel assay, respectively. Mutation analysis of HBV DNAs were detected by a differential DNA denaturation PCR assay. A3G encapsidation into HBV nucleocapsids was examined by Western blot analysis after ultracentrifugation and a co-immunoprecipitation (IP) assay between HBV core and A3G proteins.

Results: In the present study, we found that IMB-Z could considerably inhibit HBV replication in HepAD38 cells. Interestingly, IMB-Z did not alter the HBV pgRNA production but could reduce the level of core protein, viral nucleocapsids and core-associated DNA, as well as cccDNA intracellular amplification. Similar to the action of IMB-Z's inhibition of EV71 replication, we found that IMB-Z's inhibition of HBV replication is associated with increased level of A3G. Mechanistically, we demonstrated that the inhibitory effect of IMB-Z is independent on the cytidine deaminase activity of A3G and is exerted by increasing its incorporation into viral nucleocapsids.

Conclusions: Our results indicate that IMB-Z inhibits HBV through pharmacological induction A3G expression and incorporation into HBV nucleocapsids.

Keywords: APOBEC3G; IMB-Z; hepatitis B virus; incorporation.

Copyright © 2022. Published by Elsevier Ltd.

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现金
62111 元 
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30437 
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最后登录
2022-12-28 

才高八斗

3
发表于 2022-11-19 12:37 |只看该作者
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