Pevonedistat是一流的NEDD8活化酶抑制剂，是乙型肝炎病毒的有效

StephenW

Hepatology. 2018 Dec 26. doi: 10.1002/hep.30491. [Epub ahead of print]
Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, is a potent inhibitor of hepatitis B virus.
Sekiba K1, Otsuka M1, Ohno M1, Yamagami M1, Kishikawa T1, Seimiya T1, Suzuki T1, Tanaka E1, Ishibashi R1, Funato K1, Koike K1.
Author information

1
    Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Abstract

Hepatitis B virus (HBV) infection is a major health concern worldwide. To prevent HBV-related mortality, elimination of viral proteins is considered the ultimate goal of HBV treatment; however, currently available nucleos(t)ide analogs rarely achieve this goal, as viral transcription from episomal viral covalently closed circular DNA (cccDNA) is not prevented. HBV regulatory protein X was recently found to target the protein structural maintenance of chromosomes 5/6 (Smc5/6) for ubiquitination and degradation by DDB1-CUL4-ROC1 E3 ligase, resulting in enhanced viral transcription from cccDNA. This ubiquitin-dependent proteasomal pathway requires an additional ubiquitin-like protein for activation, NEDD8. Here, we show that pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, works efficiently as a novel anti-viral agent. Pevonedistat significantly restored Smc5/6 protein levels and suppressed viral transcription and protein production in the HBV minicircle system in in vitro HBV replication models and in human primary hepatocytes infected naturally with HBV. Conclusion These results indicate that pevonedistat is a promising compound to treat chronic HBV infection. This article is protected by copyright. All rights reserved.
KEYWORDS:

Chronic hepatitis B; Digital PCR; Minicircle DNA; Neddylation; Smc5/6

PMID:
    30586159
DOI:
    10.1002/hep.30491

StephenW

肝病。 2018年12月26日doi：10.1002 / hep.30491。 [提前打印]
Pevonedistat是一流的NEDD8活化酶抑制剂，是乙型肝炎病毒的有效抑制剂。
Sekiba K1，Otsuka M1，Ohno M1，Yamagami M1，Kishikawa T1，Seimiya T1，铃木T1，Tanaka E1，Ishibashi R1，Funato K1，Koike K1。
作者信息

1
    东京大学大学院医学研究科消化内科，东京，113-8655，日本。

抽象

乙型肝炎病毒（HBV）感染是全世界主要的健康问题。为了预防HBV相关的死亡，消除病毒蛋白被认为是HBV治疗的最终目标;然而，目前可用的核苷（t）ide类似物很少实现这一目标，因为不会阻止来自附加型病毒共价闭合环状DNA（cccDNA）的病毒转录。最近发现HBV调节蛋白X靶向染色体5/6（Smc5 / 6）的蛋白质结构维持，用于泛素化和DDB1-CUL4-ROC1 E3连接酶的降解，导致cccDNA的病毒转录增强。这种遍在蛋白依赖性蛋白酶体途径需要额外的泛素样蛋白激活NEDD8。在这里，我们表明pevonedistat，一流的NEDD8激活酶抑制剂，作为一种新型抗病毒剂有效地工作。 Pevonedistat在体外HBV复制模型和HBV天然感染的人原代肝细胞中显着恢复了Smc5 / 6蛋白水平并抑制了HBV小环系统中的病毒转录和蛋白质产生。结论这些结果表明，pevonedistat是治疗慢性HBV感染的有希望的化合物。本文受版权保护。版权所有。
关键词：

慢性乙型肝炎;数字PCR;小环DNA; Neddylation; SMC5 / 6

结论：
    30586159
DOI：
    10.1002 / hep.30491

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