Bardoxolone methyl as a novel potent antiviral agent against hepatitis B and C viruses in human hepatocyte cell culture systems.

Abstract

Antiviral drugs against hepatitis B virus (HBV) relieve symptoms experienced by patients with hepatitis; however, these drugs cannot eliminate HBV infection from all patients completely. On the other hand, direct antiviral agents (DAAs) against hepatitis C virus (HCV) can achieve near-complete elimination of HCV infection. However, recent reports have claimed that DAAs pose a risk for HBV reactivation among patients with HBV and HCV co-infection. This suggests that an effective anti-viral strategy for both HBV and HCV would be extremely useful. We hypothesized that an activator of nuclear factor-erythroid factor 2 (Nrf2) could be a candidate, because heme oxygenase-1 (HO-1), a product of the Nrf2-target gene, was shown to be related to suppression of genome replication in both HBV and HCV. In this study, the potential of bardoxolone methyl (BARD), an Nrf2 activator, was examined in cell culture systems against HBV and HCV. We investigated that BARD had a suppressive effect on the production of extracellular HBV DNA in several HBV culture systems. In addition, BARD treatment reduced the levels of intracellular HBV pregenome RNA (pgRNA), a transcript from the HBV genome and a template of HBV genome replication. HCV genome replication was also suppressed in HCV subgenomic replicon-bearing cells by BARD treatment. BARD might be a novel treatment for patients with HBV and HCV co-infection.