Cell Mol Gastroenterol Hepatol. 2018 Oct 24;7(2):297-312. doi: 10.1016/j.jcmgh.2018.10.010. [Epub ahead of print]
Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx-DDB1 Interaction.
Sekiba K1, Otsuka M2, Ohno M1, Yamagami M1, Kishikawa T1, Suzuki T1, Ishibashi R1, Seimiya T1, Tanaka E1, Koike K1.
Author information
1
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
2
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: [email protected].
Abstract
BACKGROUND & AIMS:
Hepatitis B virus (HBV) infection is a major health concern worldwide. Although currently used nucleos(t)ide analogs efficiently inhibit viral replication, viral proteins transcribed from the episomal viral covalently closed circular DNA (cccDNA) minichromosome continue to be expressed long-term. Because high viral RNA or antigen loads may play a biological role during this chronicity, the elimination of viral products is an ultimate goal of HBV treatment. HBV regulatory protein X (HBx) was recently found to promote transcription of cccDNA with degradation of Smc5/6 through the interaction of HBx with the host protein DDB1. Here, this protein-protein interaction was considered as a new molecular target of HBV treatment.
METHODS:
To identify candidate compounds that target the HBx-DDB1 interaction, a newly constructed split luciferase assay system was applied to comprehensive compound screening. The effects of the identified compounds on HBV transcription and cccDNA maintenance were determined using HBV minicircle DNA, which mimics HBV cccDNA, and the natural HBV infection model of human primary hepatocytes.
RESULTS:
We show that nitazoxanide (NTZ), a thiazolide anti-infective agent that has been approved by the FDA for protozoan enteritis, efficiently inhibits the HBx-DDB1 protein interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system and in human primary hepatocytes naturally infected with HBV.
CONCLUSIONS:
These results indicate that NTZ, which targets an HBV-related viral-host protein interaction, may be a promising new therapeutic agent and a step toward a functional HBV cure.