乙型肝炎病毒核心蛋白变构调节剂的作用机理及临床研发和应用前景

刘慧; 鲁凤民; 郭巨涛

doi:10.3969/j.issn.1001-5256.2022.08.005

乙型肝炎病毒核心蛋白变构调节剂的作用机理及临床研发和应用前景

DOI: 10.3969/j.issn.1001-5256.2022.08.005

刘慧^{1, 2, , ,},
鲁凤民¹,
郭巨涛²

1.
北京大学基础医学院病原生物学系暨感染病中心, 北京 100191
2.
巴鲁克布隆伯格研究所, 美国宾夕法尼亚州 18902

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：刘慧、郭巨涛负责拟定文章写作思路及文章初稿的撰写；鲁凤明、郭巨涛负责文章内容的修改并最终定稿。

详细信息

通信作者:
刘慧, liuhui5215@126.com

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出版历程
- 收稿日期: 2022-05-29
- 录用日期: 2022-07-04
- 出版日期: 2022-08-20

Mechanism of action, clinical research and development, and application prospect of hepatitis B virus core protein allosteric modulators

Hui LIU^{1, 2
, ,
,},
Fengmin LU¹,
Jutao GUO²

1.
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
2.
Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA

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Corresponding author: LIU Hui, liuhui5215@126.com(ORCID: 0000-0002-6537-8093)

摘要

摘要: HBV感染是导致慢性肝炎的主要致病因素，若不及时、有效地规范治疗，将有进一步发展为肝硬化、肝细胞癌等终末期肝病的风险。临床现有的两类抗病毒药物皆无法彻底抑制病毒复制和清除病毒转录模板，即感染肝细胞内长期存在的共价闭合环状DNA(cccDNA)，因而，慢性乙型肝炎患者需长期甚至终身服药。因此，研发新型抗HBV药物显得尤为重要。核心蛋白变构调节剂(CpAM)是一类新型抗HBV药物，其干扰HBV核衣壳装配过程，并对成熟核衣壳解聚、cccDNA形成和HBeAg的产生及分泌发挥抑制作用。因其广泛作用于病毒复制的多个环节，具备较大的应用潜力。本文主要阐述CpAM靶蛋白-核心蛋白的功能、CpAM分类、作用靶点及抗HBV机理、CpAM临床试验现状及进一步研发和应用前景。
- 乙型肝炎病毒 /
- 核心蛋白变构调节剂 /
- 临床试验
Abstract: Hepatitis B virus (HBV) infection is the main pathogenic factor for chronic hepatitis, and if it is not treated timely and effectively, it may have the risk of developing into end-stage liver diseases such as liver cirrhosis and hepatocellular carcinoma. Neither of the two types of antiviral drugs currently used in clinical practice can completely inhibit viral replication or eliminate viral transcriptional template, which means that covalently closed circular DNA (cccDNA) exists in infected liver cells for a long time, and thus patients with chronic hepatitis B require long-term or even lifelong medication. Therefore, it is of great importance to develop novel anti-HBV drugs. Core protein allosteric modulators (CpAM) are a type of novel anti-HBV drugs and can interfere with HBV nucleocapsid assembly and inhibit the depolymerization of mature nucleocapsid, the formation of cccDNA, and the biogenesis and secretion of HBeAg. CpAM have a great potential in clinical application since they act on various links of viral replication. This article reviews the function of CpAM target protein-core protein, the classification, action targets, and anti-HBV mechanism of CpAM, and the current research status, further development, and application prospect of CpAM.
- Hepatitis B Virus /
- Core Protein Allosteric Modulators /
- Clinical Trial

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图 1 CpAM在HBV复制周期中的多重抗病毒作用

注：Ⅰ型CpAM诱导Cp二聚体形成多种形态的非衣壳结构，并最终经由自噬途径被降解^[35]；Ⅱ型CpAM加速衣壳组装过程，诱导空衣壳结构产生。就结果而言，两种类型的CpAM皆抑制了pgRNA/pol向核衣壳内的包装从而抑制后续HBV DNA的复制；也促进含rcDNA核衣壳的错误解聚从而抑制了cccDNA的从头合成。除此之外，Ⅰ、Ⅱ型CpAM皆直接作用于细胞内的p17从而抑制了HBeAg的分泌。

Figure 1. Multiple anti-HBV effects of CpAM on HBV replication cycle

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表 1 代表性CpAM单一用药临床试验概况

Table 1. Overview of monotherapy for representative CpAM in clinical trial

CpAM名称	类别及特征	血清病毒学指标最大降低(log₁₀ IU/mL或拷贝/mL) (与基线相比)					当前临床试验阶段	支持企业	临床试验注册号
CpAM名称	类别及特征	HBV DNA	HBV RNA	HBsAg	HBeAg	HBcrAg	当前临床试验阶段	支持企业	临床试验注册号
GLS4JHS	Ⅰ型，非衣壳结构形成	3.5	1.78	0.33	0.43	0.5	Ⅱ期	HEC Pharma, PR China	NCT03638076，NCT04147208
ZM-H1505R		NR	NR	NR	NR	NR	Ⅰ期	ZhiMeng Biopharma, PR China	NCT04220801
QL-007		NR	NR	NR	NR	NR	Ⅱ期	Qilu Pharma, PR China	NCT03770624, NCT04157257 NCT03244085, NCT04157699
RO7049389		＜LLOQ	2.77	-0.1~0.2	-0.2~0.0	＞1	Ⅱ期	Roche, Switzerland	NCT04729309, NCT02952924, NCT04225715
NVR 3-778¹⁾	Ⅱ型，形态正常的空衣壳结构形成	1.43	1.42	1	0.09	0.13	Ⅰ b期	Novira, Janssen Pharmaceutica	NCT02112799, NCT02401737
AB-506²⁾		2.8	2.4	0.113	NR	NR	Ⅰ b期	Arbutus Biopharma	无
EDP-514		NR	NR	NR	NR	NR	Ⅰ b期	Enanta, Pharma, USA	NCT04470388, NCT04008004
ABI-H0731		2.8	2	NR	NR	NR	Ⅱ期	Assembly bioscience, USA/Beigene, China	NCT02908191
JNJ-56136379		＜LLOQ	＜LLOQ	-0.005~0.03	-0.1	≥0.5	Ⅱ期	Janssen	NCT02662712
注：NR，无报道；LLOQ，低于定量检测下限。1)后续临床试验暂停；2)后续临床试验终止。

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