新型强效衣壳组装调节剂调节乙型肝炎病毒生命周期的多个

StephenW

Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00835-18. doi: 10.1128/AAC.00835-18. [Epub ahead of print]
Novel potent capsid assembly modulators regulate multiple steps of the Hepatitis B virus life-cycle.
Lahlali T1, Berke JM2, Vergauwen K2, Foca A1, Vandyck K2, Pauwels F2, Zoulim F1,3, Durantel D4.
Author information

1
    INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France.
2
    Janssen Research & Development, Beerse, Belgium.
3
    Liver Unit, Hospices Civils de Lyon (HCL), Lyon, France.
4
    INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France [email protected].

Abstract

The assembly of hepatitis B virus (HBV) core proteins (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid assembly modulators (CAMs) induce the formation of empty-capsid or aberrant-capsid devoid of pregenomic RNA (pgRNA) and finally block rcDNA neosynthesis and virion progeny. In this study, novel CAMs JNJ-827 and JNJ-890, were found to be potent inhibitors of HBV replication with a respective half maximal effective concentration of 4.7 and 66 nM in HepG2.117 cells. Antiviral profiling in differentiated HepaRG (dHepaRG) cells and primary human hepatocytes (PHH) revealed that these compounds efficiently inhibited HBV replication, as well as de novo establishment of cccDNA. In addition to these two known effects of CAMs, we observed for the first time that a CAM, here JNJ-827, when added post-infection for a short-term period, significantly reduced HBeAg secretion without affecting the levels of cccDNA amount, transcription, and HBsAg secretion. This inhibitory activity resulted from a direct effect of JNJ-827 on HBeAg biogenesis. In a long-term treatment condition using persistently infected dHepaRG cells, JNJ-827 and JNJ-890 reduced HBsAg, concomitantly to a decrease in viral total RNA and pgRNA levels. Altogether, these data demonstrate that some CAMs could interfere with multiple functions of HBc in the viral life cycle.

PMID:
    30012770
DOI:
    10.1128/AAC.00835-18

StephenW

抗微生物剂Chemother。 2018年7月16日.pii：AAC.00835-18。 doi：10.1128 / AAC.00835-18。 [提前打印]
新型强效衣壳组装调节剂调节乙型肝炎病毒生命周期的多个步骤。
Lahlali T1，Berke JM2，Vergauwen K2，Foca A1，Vandyck K2，Pauwels F2，Zoulim F1,3，Durantel D4。
作者信息

1
    INSERM，U1052，里昂癌症研究中心（CRCL），里昂大学（UCBL1），CNRS UMR_5286，法国里昂莱昂贝拉德中心。
2
    Janssen研发，比利时Beerse。
3
    肝脏单位，Hospices Civils de Lyon（HCL），里昂，法国。
4
    INSERM，U1052，里昂癌症研究中心（CRCL），里昂大学（UCBL1），CNRS UMR_5286，法国里昂LéonBérard中心[email protected]。

抽象

将乙型肝炎病毒（HBV）核心蛋白（HBc）组装成衣壳是病毒复制的关键步骤。 HBc在HBV生命周期中具有多种功能，这使其成为抗病毒治疗的有吸引力的靶标。衣壳装配调节剂（CAM）诱导缺乏前基因组RNA（pgRNA）的空衣壳或异常衣壳的形成，并最终阻断rcDNA新合成和病毒粒子后代。在该研究中，发现新型CAMs JNJ-827和JNJ-890是HBV复制的有效抑制剂，在HepG2.117细胞中各自的半最大有效浓度为4.7和66nM。在分化的HepaRG（dHepaRG）细胞和原代人肝细胞（PHH）中的抗病毒特征分析显示这些化合物有效地抑制HBV复制，以及从头建立cccDNA。除了CAMs的这两种已知作用外，我们首次观察到CAM（这里是JNJ-827）在短期感染后加入，显着降低了HBeAg的分泌而不影响cccDNA的水平，转录，和HBsAg分泌。这种抑制活性是由JNJ-827对HBeAg生物发生的直接作用引起的。在使用持续感染的dHepaRG细胞的长期治疗条件下，JNJ-827和JNJ-890降低了HBsAg，同时降低了病毒总RNA和pgRNA水平。总之，这些数据表明一些CAM可能在病毒生命周期中干扰HBc的多种功能。

结论：
    30012770
DOI：
    10.1128 / AAC.00835-18

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