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
Mechanism of action, clinical research and development, and application prospect of hepatitis B virus core protein allosteric modulators
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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。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.
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Key words:
- 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
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 HBV DNA HBV RNA HBsAg HBeAg HBcrAg 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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