School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, 06125, Republic of Korea.
Nat Commun. 2019 May 16;10(1):2184. doi: 10.1038/s41467-019-10200-5.
Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.
慢性乙型肝炎病毒 (HBV) 感染可导致肝硬化和肝细胞癌,因此是一个严重的公共卫生问题。目前,受感染的患者接受核苷/核苷酸类似物和干扰素 α 的治疗,但这种方法并不能治愈疾病。在这里,我们筛选了 978 种美国食品和药物管理局批准的化合物,以评估它们抑制 HBV 表达的 HepG2.2.15 细胞中 HBV 复制的能力。我们发现,环吡酮胺,一种合成抗真菌剂,通过阻断 HBV 衣壳组装强烈抑制细胞和小鼠中的 HBV 复制。HBV 核心蛋白和环吡酮胺复合物的晶体结构揭示了在二聚体-二聚体界面处的独特结合模式。环吡酮胺与核苷/核苷酸类似物协同作用,可防止细胞和人源化肝脏小鼠模型中的 HBV 复制。因此,口服给予环吡酮胺可能通过阻断 HBV 衣壳组装为治疗慢性 HBV 感染提供新的机会。