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

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.

Liver-specific mono-unsaturated fatty acid synthase-1 inhibitor for anti-hepatitis C treatment.

Recently, direct antiviral agents against hepatitis C virus (HCV) infection have been developed as highly effective anti-HCV drugs. However, the appearance of resistant viruses against direct anti-viral agents is an unsolved problem. One of the strategies considered to suppress the emergence of the drug-resistant viruses is to use drugs inhibiting the host factor, which contributes to HCV proliferation, in combination with direct anti-viral agents. The replication complex was reported to be present in the membranous compartment in the cells. Thus, lipid metabolism modulators are good candidates to regulate virus assembly and HCV replication. Recent studies have shown that stearoyl-CoA desaturase (SCD), an enzyme for long-chain mono-unsaturated fatty acid (LCMUFA) synthesis, is a key factor that defines HCV replication efficiency. Systemic exposure to SCD-1 inhibor induces some side effects in the eyes and skin. Thus, systemic SCD-1 inhibitors are considered inappropriate for HCV therapy. To avoid the side effects of systemic SCD-1 inhibitors, the liver-specific SCD-1 inhibitor, MK8245, was synthesized; it showed antidiabetic effects in diabetic model mice with no side effects. In the phase 1 clinical study on measurement of MK8245 tolerability, no significant side effects were reported (ClinicalTrials.gov Identifier: NCT00790556). Therefore, we thought liver-specific SCD-1 inhibitors would be suitable agents for HCV-infected patients. MK8245 was evaluated using recombinant HCV culture systems. Considering current HCV treatments, to avoid the emergence of direct anti-viral agents-resistant viruses, combination therapy with direct anti-viral agents and host-targeted agents would be optimal. With this viewpoint, we confirmed MK8245's additive or synergistic anti-HCV effects on current direct anti-viral agents and interferon-alpha therapy. The results suggest that MK8245 is an option for anti-HCV multi-drug therapy with a low risk of emergence of drug-resistant HCV without significant side effects.