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Pevonedistat, a first‐in‐class NEDD8‐activating enzyme inhibitor, is a potent inhibitor of hepatitis B virus
Kazuma Sekiba
Motoyuki Otsuka
Motoko Ohno
Mari Yamagami
Takahiro Kishikawa
Takahiro Seimiya
Tatsunori Suzuki
Eri Tanaka
Rei Ishibashi
Kazuyoshi Funato
Kazuhiko Koike
First published: 26 December 2018
https://doi.org/10.1002/hep.30491
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.30491
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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.
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发表于 2019-1-11 17:24