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 EC₅₀ 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.

尽管很难从患者体内完全消除共价闭合的环状DNA（cccDNA），但目前可用的用于慢性感染乙型肝炎病毒（HBV）的抗病毒药是聚乙二醇化干扰素-α和核苷/核苷酸类似物。为了鉴定靶向HBV核心启动子的抗病毒化合物，在HBV核心启动子的控制下，使用表达萤火虫荧光素酶的细胞系筛选了15种来自海洋生物的萜烯。Metachromin A是一种从海生海绵Dactylospongia metachromia中分离出的倍半萜烯，在被测化合物中以最高水平抑制了病毒启动子的活性，并以EC ₅₀抑制了HBV的产生。不论干扰素信号传导和细胞毒性如何，均值为0.8μM。对结构-活性关系的分析表明，对苯二酚A的对苯二酚部分以及碳数5和-9处的双键对于抗HBV活性至关重要。此外，变色蛋白A降低了肝核因子4α的蛋白水平，但没有降低RNA水平，这主要上调了增强子I / X启动子和增强子II /核心启动子的活性。这些结果表明，变色蛋白A可通过破坏病毒启动子活性来抑制HBV产生。无论残留的cccDNA如何，靶向病毒启动子的抗病毒药物均可缓解HBV相关疾病。