pevonedistat and Hepatitis-B

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.

Topics: Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Cyclopentanes; Drug Evaluation, Preclinical; HEK293 Cells; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Primary Cell Culture; Pyrimidines; Ubiquitin-Activating Enzymes; Ubiquitin-Protein Ligases; Virus Replication