靶向多功能HBV核心蛋白可潜在治愈慢性乙型肝炎

StephenW

Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B
Usha Viswanathan  1 , Nagraj Mani  2 , Zhanying Hu  1 , Haiqun Ban  1 , Yanming Du  1 , Jin Hu  1 , Jinhong Chang  1 , Ju-Tao Guo  3
Affiliations
Affiliations

    1
    Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 28902, USA.
    2
    Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA.
    3
    Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 28902, USA. Electronic address: [email protected].

    PMID: 32818519 DOI: 10.1016/j.antiviral.2020.104917

Abstract

The core (capsid) protein of hepatitis B virus (HBV) is the building block of nucleocapsids where viral DNA reverse transcriptional replication takes place and mediates virus-host cell interaction important for the persistence of HBV infection. The pleiotropic role of core protein (Cp) in HBV replication makes it an attractive target for antiviral therapies of chronic hepatitis B, a disease that affects more than 257 million people worldwide without a cure. Recent clinical studies indicate that core protein allosteric modulators (CpAMs) have a great promise as a key component of hepatitis B curative therapies. Particularly, it has been demonstrated that modulation of Cp dimer-dimer interactions by several chemical series of CpAMs not only inhibit nucleocapsid assembly and viral DNA replication, but also induce the disassembly of double-stranded DNA-containing nucleocapsids to prevent the synthesis of cccDNA. Moreover, the different chemotypes of CpAMs modulate Cp assembly by interaction with distinct amino acid residues at the HAP pocket between Cp dimer-dimer interfaces, which results in the assembly of Cp dimers into either non-capsid Cp polymers (type I CpAMs) or empty capsids with distinct physical property (type II CpAMs). The different CpAMs also differentially modulate Cp metabolism and subcellular distribution, which may impact cccDNA metabolism and host antiviral immune responses, the critical factors for the cure of chronic HBV infection. This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on "Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."

Keywords: Capsid; Core protein allosteric modulators; Hepatitis B virus; Nucleocapsid; cccDNA.

Copyright © 2020 Elsevier B.V. All rights reserved.

StephenW

靶向多功能HBV核心蛋白可潜在治愈慢性乙型肝炎
Usha Viswanathan 1，Nagraj Mani 2，胡占英1，海群班1，杜艳明1，金胡1，金宏昌1，郭菊涛3
隶属关系
隶属关系

    1个
    Baruch S.Blumberg研究所，3805 Old Easton Road，Doylestown，PA，28902，美国。
    2
    Arbutus Biopharma Inc.，701 Veterans Circle，Warminster，PA，18974，USA。
    3
    Baruch S.Blumberg研究所，3805 Old Easton Road，Doylestown，PA，28902，美国。电子地址：[email protected]。

    PMID：32818519 DOI：10.1016 / j.antiviral.2020.104917

抽象

乙型肝炎病毒（HBV）的核心（衣壳）蛋白是核衣壳的构建基，病毒DNA发生逆转录复制并介导了病毒与宿主细胞之间的相互作用，对持久性HBV感染至关重要。核心蛋白（Cp）在HBV复制中的多效性使其成为慢性乙型肝炎的抗病毒治疗的有吸引力的靶标，该疾病在全球无法治愈的情况下影响超过2.57亿人。最近的临床研究表明，核心蛋白变构调节剂（CpAM）作为乙肝治疗的关键成分具有广阔的前景。特别地，已经证明，通过几个化学系列的CpAM调节Cp二聚体-二聚体相互作用不仅抑制核衣壳装配和病毒DNA复制，而且还诱导了含双链DNA的核衣壳的分解，从而阻止了cccDNA的合成。此外，CpAM的不同化学型通过与Cp二聚体-二聚体界面之间的HAP口袋处的不同氨基酸残基相互作用而调节Cp装配，从而导致Cp二聚体装配成非衣壳Cp聚合物（I型CpAMs）或空的具有不同物理性质的衣壳（II型CpAM）。不同的CpAM还可以差异地调节Cp代谢和亚细胞分布，这可能会影响cccDNA代谢并产生抗病毒免疫应答，这是治愈慢性HBV感染的关键因素。这篇综述文章重点介绍了在HBV复制周期中核心蛋白的结构和功能，CpAMs的作用方式以及在靶向蛋白的核心抗病毒药的发现和开发方面的最新研究进展。本文是“关于治疗HBV和HDV感染的广泛免疫和直接作用抗病毒方法”抗病毒研究研讨会的一部分。

关键字：衣壳；核心蛋白变构调节剂；乙型肝炎病毒;核仁; cccDNA。