Discovery of a novel sodium taurocholate cotransporting polypeptide (NTCP) inhibitor: Design, synthesis, and anti-proliferative activities
Discovery of a novel sodium taurocholate cotransporting polypeptide (NTCP) inhibitor: Design, synthesis, and anti-proliferative activities
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新型牛磺胆酸钠共转运多肽 (NTCP) 抑制剂的发现：设计、合成和抗增殖活性
DOI：
10.1016/j.cclet.2020.03.017
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发表时间：
2020
影响因子：
9.1
通讯作者：
Ouyang Liang
中科院分区：
文献类型：
--
作者：
Xiang Honggang;Chen Yanmei;Zhang Jifa;Zhang Jin;Pan Dabo;Liu Bo;Ouyang Liang
牛磺胆酸钠共转运多肽 (NTCP) 被确定为 HBV 进入的功能性受体，负责在 HBV 生命周期中上调 HBV 转录。此外，NTCP还与HBV诱导的肝细胞癌（HCC）的进展有关。因此，NTCP靶向进入抑制剂被提议在HBV诱导的肝癌治疗中抑制HBV感染和复制。在此，我们综合硅筛选和化学合成获得了小分子NTCP抑制剂B7，其在体外表现出中等程度的抗HepG2细胞增殖活性和抗HBV活性。此外，CETSA 测定、分子对接和 MD 模拟验证了 B7 可以与 NTCP 结合。此外，蛋白质印迹分析表明，B7 通过增加 HepG2 细胞中 Bax 和 caspase 3 裂解的表达以及减少 Bcl-2 的表达来诱导细胞凋亡。综上所述，我们的研究确定 B7 是一种具有抗增殖活性的新型 NTCP 抑制剂，这可能为 HCC 治疗提供新的机会。
Sodium taurocholate cotransporting polypeptide (NTCP) is identified as the functional receptor for HBV entry, which is responsible for upregulated HBV transcription in the HBV life cycle. Besides, NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma (HCC). Thereby, NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy. Herein, we integratedin silicoscreening and chemical synthesis to obtain a small-molecule NTCP inhibitorB7, which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activityin vitro. Additionally, CETSA assay, molecular docking, and MD simulation validated thatB7could bind to NTCP. Furthermore, western blot analysis demonstrated thatB7induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells. Taken together, our study identifiedB7as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.