Ezetimibe inhibits dengue virus infection in Huh-7 cells by blocking the cholesterol transporter Niemann-Pick C1-like 1 receptor
Ezetimibe inhibits dengue virus infection in Huh-7 cells by blocking the cholesterol transporter Niemann-Pick C1-like 1 receptor
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DOI：
10.1016/j.antiviral.2018.10.024
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发表时间：
2018-12-01
影响因子：
7.6
通讯作者：
Maria del Angel, Rosa
中科院分区：
文献类型：
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作者：
Fidel Osuna-Ramos, Juan;Manuel Reyes-Ruiz, Jose;Maria del Angel, Rosa
尽管登革病毒（DENV）感染对人类健康很重要，但目前还没有针对该感染的完全有效的疫苗或抗病毒治疗方法。由于脂质如胆固醇在DENV感染期间是必需的，因此其摄取和合成在感染细胞中增加。依折麦布是一种FDA批准的药物，通过抑制肠细胞和肝细胞膜上表达的Niemman-Pick C1样1（NPC 1 L1）受体的内吞作用来降低胆固醇摄取。我们的研究结果表明，在登革病毒感染过程中，Huh-7细胞表面NPC 1 L1的量增加，这与胆固醇水平的增加相关。用浓度高达50 μ M的依折麦布阻断NPC 1 L1不会降低细胞活力，但会降低总细胞胆固醇、感染细胞的百分比、病毒产量、病毒RNA和蛋白质合成，而不影响DENV结合和/或进入Huh-7细胞。此外，依折麦布抑制DENV复制复合物形成和脂滴蓄积。所有这些结果表明依折麦布是抑制DENV感染的优良药物，并证实胆固醇是抑制病毒感染的关键靶点。
Despite the importance of Dengue virus (DENV) infection in human health, there is not a fully effective vaccine or antiviral treatment against the infection. Since lipids such as cholesterol are required during DENV infection, its uptake and synthesis are increased in infected cells. Ezetimibe is an FDA-approved drug that reduces cholesterol uptake by inhibiting the endocytosis through Niemman-Pick C1-Like 1 (NPC1L1) receptor, expressed on the membrane of enterocytes and hepatocytes. Our results indicate that an increase in the amount of NPC1L1 occurs on the surface of Huh-7 cells during DENV infection, which correlates with an increase in cholesterol levels. Blockage of NPC1L1 with ezetimibe in concentrations up to 50 mu M does not reduce cell viability but diminished total cellular cholesterol, the percentage of infected cells, viral yield, viral RNA and protein synthesis without affecting DENV binding and/or entry to Huh-7 cells. Moreover, ezetimibe inhibited DENV replicative complex formation and lipid droplets accumulation. All these results indicate that ezetimibe is an excellent drug to inhibit DENV infection and confirm that cholesterol is a key target to inhibit viral infection.