Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus
Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus
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DOI：
10.1002/hep.30491
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发表时间：
2019-05-01
期刊：
影响因子：
13.5
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Sekiba, Kazuma;Otsuka, Motoyuki;Koike, Kazuhiko
B型肝炎病毒（HBV）感染是世界范围内的主要健康问题。为了预防HBV相关的死亡率，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（酸）类似物很少实现这一目标，因为不能阻止病毒从游离型病毒共价闭合环状DNA（cccDNA）的转录。最近发现HBV调节蛋白X靶向染色体5/6（Smc 5/6）的蛋白质结构维持，用于通过DDB 1-CUL 4-R 0 C1 E3连接酶的泛素化和降解，导致从cccDNA的增强的病毒转录。这种泛素依赖性蛋白酶体途径需要额外的泛素样蛋白来激活，即神经元前体细胞表达的发育下调蛋白8（NEDD 8）。在这里，我们证明了pevonedistat（一种NEDD 8激活酶抑制剂）作为抗病毒药有效。在体外HBV复制模型和自然感染HBV的人原代肝细胞中，Pevonedistat显著恢复了Smc 5/6蛋白水平，并抑制了HBV小环系统中的病毒转录和蛋白产生。结论：这些结果表明，pevonedistat是一种有前景的治疗慢性HBV感染的化合物。
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, neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8). Here, we show that pevonedistat, a NEDD8-activating enzyme inhibitor, works efficiently as an antiviral 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.