Inhibitory effects of metachromin A on hepatitis B virus production via impairment of the viral promoter activity

摘要

Abstract The currently available antiviral agents for chronic infection with hepatitis B virus (HBV) are pegylated interferon-α and nucleoside/nucleotide analogues, although it has been difficult to completely eliminate covalently closed circular DNA (cccDNA) from patients. To identify an antiviral compound targeting HBV core promoter, 15 terpenes originating from marine organisms were screened using a cell line expressing firefly luciferase under the control of the HBV core promoter. Metachromin A, which is a merosesquiterpene isolated from the marine sponge Dactylospongia metachromia , inhibited the viral promoter activity at the highest level among the tested compounds, and suppressed HBV production with an EC 50 value of 0.8?μM regardless of interferon signaling and cytotoxicity. The analysis on the structure-activity relationship revealed that the hydroquinone moiety, and the double bonds at carbon numbers-5 and -9 in metachromin A are crucial for anti-HBV activity. Furthermore, metachromin A reduced the protein level but not the RNA level of hepatic nuclear factor 4α, which mainly upregulates the activities of enhancer I/X promoter and enhancer II/core promoter. These results suggest that metachromin A can inhibit HBV production via impairment of the viral promoter activity. Antiviral agents targeting the viral promoter may ameliorate HBV-related disorders regardless of remaining cccDNA. Highlights ? Metachromin A was identified as an inhibitor of HBV core promoter among 15 terpenes purified from marine organisms. ? Metachromin A suppressed HBV production and the viral replication. ? Metachromin A reduced the amount of HNF4α protein, which is responsible for the activity of the viral promoter. ? Metachromin A exhibits anti-HBV activity via impairment of the viral promoter activity.