A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation.
A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation.
复制标题
一种新型哒嗪酮衍生物通过诱导无基因组衣壳形成来抑制乙型肝炎病毒复制。
DOI：
10.1128/aac.01558-15
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发表时间：
2015
影响因子：
4.9
通讯作者：
Zuo Jian-Ping
中科院分区：
文献类型：
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作者：
Wang Ya-Juan;Lu Dong;Xu Yi-Bin;Xing Wei-Qiang;Tong Xian-Kun;Wang Gui-Feng;Feng Chun-Lan;He Pei-Lan;Yang Li;Tang Wei;Hu You-Hong;Zuo Jian-Ping
在这里，我们首先确定了一个新的哒嗪酮衍生物，化合物3711，作为一个非核苷类B肝炎病毒（HBV）抑制剂在细胞模型系统。3711在1.5 ± 0.2 μM时使细胞外HBV DNA水平降低50%（50%抑制浓度[IC 50]），在1.9 ± 0.1 μM时使细胞内DNA水平降低50%（IC 50），这表明在远低于毒性相关水平的水平下具有抗病毒活性。3 TC/ETV双重耐药L180 M/M204 I突变株和阿德福韦酯（ADV）耐药A181 T/N236 T突变株对3711的敏感性与野生型HBV相同。3711处理诱导无基因组衣壳的形成，其中一部分在1.8%天然琼脂糖凝胶上迁移更快。诱导的无基因组衣壳沉降更缓慢，在等密度CsCl梯度离心没有显着的形态变化。3711处理降低了分泌的包膜病毒体和上清液中的裸病毒颗粒中所含的HBV DNA水平。3711可以干扰核心蛋白（Cp）组装结构域的衣壳形成。一个Cp V124 W突变体，加强衣壳二聚体间的相互作用，概括了3711对衣壳组装的影响。哒嗪酮衍生物3711是一种新型的化学实体和HBV抑制剂，可能为对抗慢性HBV感染提供新的机会。
Here we first identified a novel pyridazinone derivative, compound 3711, as a nonnucleosidic hepatitis B virus (HBV) inhibitor in a cell model system. 3711 decreased extracellular HBV DNA levels by 50% (50% inhibitory concentration [IC50]) at 1.5 ± 0.2 μM and intracellular DNA levels at 1.9 ± 0.1 μM, which demonstrated antiviral activity at levels far below those associated with toxicity. Both the 3TC/ETV dually resistant L180M/M204I mutant and the adefovir (ADV)-resistant A181T/N236T mutant were as susceptible to 3711 as wild-type HBV. 3711 treatment induced the formation of genome-free capsids, a portion of which migrated faster on 1.8% native agarose gel. The induced genome-free capsids sedimented more slowly in isopycnic CsCl gradient centrifugation without significant morphological changes. 3711 treatment decreased levels of HBV DNA contained in both secreted enveloped virion and naked virus particles in supernatant. 3711 could interfere with capsid formation of the core protein (Cp) assembly domain. A Cp V124W mutant, which strengthens capsid interdimer interactions, recapitulated the effect of 3711 on capsid assembly. Pyridazinone derivative 3711, a novel chemical entity and HBV inhibitor, may provide a new opportunity to combat chronic HBV infection.