Amentoflavone inhibits hepatitis B virus infection via the suppression of preS1 binding to host cells
Amentoflavone inhibits hepatitis B virus infection via the suppression of preS1 binding to host cells
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穗花杉双黄酮通过抑制宿主细胞与前S1结合抑制B型肝炎病毒感染
DOI：
10.1111/1348-0421.13064
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发表时间：
2023-03
影响因子：
2.6
通讯作者：
Chie Aoki-Utsubo;Puguh Indrasetiawan;Kento Fukano;Masami Muramatsu;N. Artanti;M. Hanafi;H. Hotta-
中科院分区：
文献类型：
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作者：
Chie Aoki-Utsubo;Puguh Indrasetiawan;Kento Fukano;Masami Muramatsu;N. Artanti;M. Hanafi;H. Hotta-
乙型肝炎病毒（HBV）是慢性肝炎、肝硬化和肝细胞癌的主要原因。目前慢性乙型肝炎的治疗药物使用干扰素和核苷类似物；然而，它们的功效是有限的。因此，迫切需要开发新的抗病毒药物来治疗乙型肝炎。在这项研究中，我们确定了一种植物源性多酚生物类黄酮，即穗花果黄酮，作为一种新的抗乙型肝炎化合物。穗花果黄酮治疗剂量依赖性地抑制 HBV 易感细胞 HepG2-hNTCP-C4 和原代人肝细胞 PXB 细胞的 HBV 感染。作用模式研究表明，穗花果黄酮抑制病毒进入步骤，但不抑制病毒内化和早期复制过程。穗花黄酮抑制 HBV 颗粒以及 HBV preS1 肽与 HepG2-hNTCP-C4 细胞的附着。转运蛋白测定表明，穗花黄酮部分抑制牛磺胆酸钠共转运多肽（NTCP）介导的胆汁酸的摄取。此外，还检查了各种穗花果黄酮类似物对 HBV 感染的 HepG2-hNTCP-C4 细胞产生 HBs 和 HBe 的影响。鲁布斯塔黄酮表现出与穗花果黄酮和穗花果黄酮-7,4',4‴-三甲醚衍生物（sciadopitysin）相当的抗 HBV 活性，具有中等的抗 HBV 活性。铜黄酮或单体类黄酮芹菜素没有表现出抗病毒活性。穗花果黄酮及其结构相关的双黄酮类化合物可能为设计针对 NTCP 的新型抗 HBV 药物抑制剂提供潜在的药物支架。
Hepatitis B virus (HBV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Current therapeutic drugs for chronic HBV infection use IFN and nucleos(t)ide analogs; however, their efficacy is limited. Thus, there is an urgent need to develop new antivirals for HBV therapy. In this study, we identified a plant‐derived polyphenolic bioflavonoid, amentoflavone, as a new anti‐HBV compound. Amentoflavone treatment dose‐dependently inhibited HBV infection in HBV‐susceptible cells with HepG2‐hNTCP‐C4 and primary human hepatocyte PXB‐cells. A mode‐of‐action study showed that amentoflavone inhibits the viral entry step, but not the viral internalization and early replication processes. Attachment of HBV particles as well as HBV preS1 peptide to HepG2‐hNTCP‐C4 cells was inhibited by amentoflavone. The transporter assay revealed that amentoflavone partly inhibits uptake of sodium taurocholate cotransporting polypeptide (NTCP)–mediated bile acid. Furthermore, effect of various amentoflavone analogs on HBs and HBe production from HBV‐infected HepG2‐hNTCP‐C4 cells was examined. Robustaflavone exhibited comparable anti‐HBV activity to that of amentoflavone and an amentoflavone‐7,4', 4‴‐trimethyl ether derivative (sciadopitysin) with moderate anti‐HBV activity. Cupressuflavone or the monomeric flavonoid apigenin did not exhibit the antiviral activity. Amentoflavone and its structurally related biflavonoids may provide a potential drug scaffold in the design of a new anti‐HBV drug inhibitor targeting NTCP.