Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, South Korea.
Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, 06125, South Korea.
Virus Res. 2019 Apr 2;263:102-111. doi: 10.1016/j.virusres.2019.01.004. Epub 2019 Jan 9.
Hepatitis B virus (HBV) infection is a major risk factor for chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. While multiple hepatitis B drugs have been developed, build up of drug resistance during treatment or weak efficacies observed in some cases have limited their application. Therefore, there is an urgent need to develop substitutional pharmacological agents for HBV-infected individuals. Here, we identified cetylpyridinium chloride (CPC) as a novel inhibitor of HBV. Using computational docking of CPC to core protein, microscale thermophoresis analysis of CPC binding to viral nucleocapsids, and in vitro nucleocapsid formation assays, we found that CPC interacts with dimeric viral nucleocapsid protein (known as core protein or HBcAg) specifically. Compared with other HBV inhibitors, such as benzenesulfonamide (BS) and sulfanilamide (SA), CPC achieved significantly better reduction of HBV particle number in HepG2.2.15 cell line, a derivative of human HCC cells that stably expresses HBV. CPC also inhibited HBV replication in mouse hydrodynamic model system. Taken together, our results show that CPC inhibits capsid assembly and leads to reduced HBV biogenesis. Thus, CPC is an effective pharmacological agent that can reduce HBV particles.
乙型肝炎病毒 (HBV) 感染是全球慢性肝病、肝硬化和肝细胞癌 (HCC) 的主要危险因素。虽然已经开发出多种乙型肝炎药物，但在治疗过程中药物耐药性的产生或在某些情况下观察到的疗效减弱限制了它们的应用。因此，迫切需要为感染乙型肝炎病毒的个体开发替代药物。在这里，我们发现氯化十六烷基吡啶 (CPC) 是一种新型的乙型肝炎病毒抑制剂。通过 CPC 与核心蛋白的计算对接、CPC 与病毒核衣壳结合的微量热泳动分析以及体外核衣壳形成测定，我们发现 CPC 与二聚体病毒核衣壳蛋白（称为核心蛋白或 HBcAg）特异性相互作用。与其他乙型肝炎病毒抑制剂（如苯磺酰胺 (BS) 和磺胺酰胺 (SA)）相比，CPC 在 HepG2.2.15 细胞系（一种稳定表达乙型肝炎病毒的人肝癌细胞系）中显著降低了乙型肝炎病毒颗粒数。CPC 还抑制了小鼠水力动力学模型系统中的乙型肝炎病毒复制。总之，我们的结果表明，CPC 抑制衣壳组装并导致乙型肝炎病毒生物发生减少。因此，CPC 是一种有效的药物制剂，可以减少乙型肝炎病毒颗粒。
