Junceellolide B, a novel inhibitor of Hepatitis B virus
Junceellolide B, a novel inhibitor of Hepatitis B virus
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Junceellolide B，一种新型乙型肝炎病毒抑制剂
DOI：
10.1016/j.bmc.2020.115603
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发表时间：
2020
影响因子：
3.5
通讯作者：
Wenhan Lin
中科院分区：
文献类型：
--
作者：
Xiaodan Li;Hui Liu;Wei Cheng;Jie Wang;He Zhang;Fengmin Lu;Xiangmei Chen;Wenhan Lin
HBV感染是肝脏疾病的常见原因，在世界范围内负担很高。目前的治疗策略依赖于干扰素和核苷类药物，但功能性治愈有限。在这项研究中，从内部库中进行基于结构的海洋天然产物的筛选，以命中HBV抑制剂，并且柳珊瑚衍生的briarane型二萜类化合物在HepAD 38细胞中显示出对HBV DNA复制的抑制作用。构效关系初步分析表明，具有3E，5（16）-二烯和C-6位氯取代的briarane基支架是抗HBV活性所必需的。Junceellulin B是一种有效的HBV抑制剂，其以剂量依赖性方式有效减少HBV感染的HepG 2-NTCP细胞中HBsAg和HBeAg的产生（p< 0.001）。在HepAD 38细胞中，它还显著降低了HBV DNA、HBV RNA和HBeAg的分泌，其EC 50值分别为0.83、2.87和7.75 μM。机制上，芥菜素B有效抑制HBV RNA转录而不促进HBV RNA降解。RNA-seq分析表明，芥菜型油菜素B显著减少HBV cccDNA转录产物，同时稳定下调RNA聚合酶II相关宿主转录因子（ZBED 6和ZBTB 7 B）的表达。这些结果表明，Junceellantase B是cccDNA的转录抑制剂，并且是开发新的抗HBV药物的有希望的先导。
HBV infection is a common cause of liver disease with a high burden worldwide. Current therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure. In this study, a structure-based screening of marine natural products from an in-house library was performed to hit HBV inhibitors, and the gorgonian-derived briarane-type diterpenoids showed inhibitory effects against HBV DNA replication in HepAD38 cells. Preliminary analyses of structure–activity relationship demonstrated that a briarane-based scaffold with an 3E,5(16)-diene and a chlorine-substitution at C-6 is required for the anti-HBV activity. Junceellolide B is one of the potent HBV inhibitors exhibiting efficient reduction of HBsAg and HBeAg production in HBV infected HepG2-NTCP cells with a dose-dependent manner (p< 0.001). It also significantly reduced the secreted HBV DNA, HBV RNA, and HBeAg in HepAD38 cells with the EC50values of 0.83, 2.87 and 7.75 μM, respectively. Mechanistically, junceellolide B potently inhibited HBV RNA transcription without promoting HBV RNA degradation. RNA-seq analysis indicated that junceellolide B significantly decreased HBV cccDNA-transcripted products accompanying stable down-regulation of the expression of RNA polymerase II related host transcription factors (ZBED6 and ZBTB7B). These findings suggest junceellolide B to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.