氯化十六烷基吡啶与乙型肝炎病毒核心蛋白的相互作用抑制

StephenW

Virus Res. 2019 Jan 9. pii: S0168-1702(18)30719-6. doi: 10.1016/j.virusres.2019.01.004. [Epub ahead of print]
Cetylpyridinium chloride interaction with the Hepatitis B virus core protein inhibits capsid assembly.
Seo HW1, Seo JP1, Cho Y2, Ko E1, Kim YJ3, Jung G4.
Author information

1
    Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, South Korea.
2
    Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, 06125, South Korea.
3
    Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
4
    Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, South Korea. Electronic address: [email protected].

Abstract

Hepatitis B virus (HBV) infection is a major risk factor for chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. While multiple hepatitis B drugs have been developed, build up of drug resistance during treatment or weak efficacies observed in some cases have limited their application. Therefore, there is an urgent need to develop substitutional pharmacological agents for HBV-infected individuals. Here, we identified cetylpyridinium chloride (CPC) as a novel inhibitor of HBV. Using computational docking of CPC to core protein, microscale thermophoresis analysis of CPC binding to viral nucleocapsids, and in vitro nucleocapsid formation assays, we found that CPC interacts with dimeric viral nucleocapsid protein (known as core protein or HBcAg) specifically. Compared with other HBV inhibitors, such as benzenesulfonamide (BS) and sulfanilamide (SA), CPC achieved significantly better reduction of HBV particle number in HepG2.2.15 cell line, a derivative of human HCC cells that stably expresses HBV. CPC also inhibited HBV replication in mouse hydrodynamic model system. Taken together, our results show that CPC inhibits capsid assembly and leads to reduced HBV biogenesis. Thus, CPC is an effective pharmacological agent that can reduce HBV particles.

Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:

antiviral; capsid assembly inhibitor; cetylpyridinium chloride (CPC); drug synergism; hepatitis B virus (HBV)

PMID:
    30639191
DOI:
    10.1016/j.virusres.2019.01.004

StephenW

病毒资源2019年1月9日.pii：S0168-1702（18）30719-6。 doi：10.1016 / j.virusres.2019.01.004。 [提前打印]
氯化十六烷基吡啶与乙型肝炎病毒核心蛋白的相互作用抑制衣壳组装。
Seo HW1，Seo JP1，Cho Y2，Ko E1，Kim YJ3，Jung G4。
作者信息

1
    首尔国立大学自然科学学院生物科学系，韩国首尔冠岳区冠岳路599号，151-747。
2
    CHA大学医学院CHA江南医学中心内科，首尔，06125，韩国。
3
    首尔国立大学医学院内科和肝脏研究所，韩国首尔03080。
4
    首尔国立大学自然科学学院生物科学系，韩国首尔冠岳区冠岳路599号，151-747。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）感染是全世界慢性肝病，肝硬化和肝细胞癌（HCC）的主要危险因素。虽然已开发出多种乙型肝炎药物，但在治疗期间积累的耐药性或在某些情况下观察到的弱效应限制了它们的应用。因此，迫切需要开发用于HBV感染个体的取代药理学试剂。在这里，我们确定氯化十六烷基吡啶（CPC）作为HBV的新型抑制剂。使用CPC与核心蛋白的计算对接，CPC与病毒核衣壳结合的微型热泳分析，以及体外核衣壳形成测定，我们发现CPC特异性地与二聚体病毒核衣壳蛋白（称为核心蛋白或HBcAg）相互作用。与其他HBV抑制剂（如苯磺酰胺（BS）和磺胺（SA））相比，CPC在HepG2.2.15细胞系中获得了明显更好的HBV颗粒数减少，HepG2.2.15细胞系是稳定表达HBV的人HCC细胞的衍生物。 CPC还抑制小鼠水动力模型系统中的HBV复制。总之，我们的结果表明CPC抑制衣壳组装并导致HBV生物合成减少。因此，CPC是一种可以减少HBV颗粒的有效药物。

版权所有©2019。Elsevier B.V.
关键词：

抗病毒;衣壳组装抑制剂;氯化十六烷基吡啶（CPC）;药物协同作用;乙型肝炎病毒（HBV）

结论：
    30639191
DOI：
    10.1016 / j.virusres.2019.01.004