Pevonedistat, a Neuronal Precursor Cell‐Expressed Developmentally Down‐Regulated Protein 8–Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus

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.