Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host-targeting agents.
Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host-targeting agents.
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内源性大麻素 CB1 拮抗剂可抑制丙型肝炎病毒的产生，提供一类新型抗病毒宿主靶向药物。
DOI：
10.1099/vir.0.067231-0
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Douglas MW.
中科院分区：
文献类型：
--
作者：
Shahidi M;Tay ES;Read SA;Ramezani-Moghadam M;Chayama K;George J;Douglas MW.
直接作用的抗病毒药物显着改善了慢性丙型肝炎（CHC）的治疗结果，但副作用，耐药性和成本意味着仍然需要更好的治疗。脂质代谢与丙型肝炎病毒（HCV）复制密切相关，内源性大麻素是脂质稳态的主要调节剂。大麻素1（CB 1）受体介导肝脏中的这些作用。我们先前已经显示了CHC患者肝脏和HCV细胞培养模型中CB 1受体的上调。在这里，我们研究了CB 1阻断是否抑制HCV复制。在HCV株JFH 1细胞培养物和亚基因组复制子模型中检查了CB 1拮抗剂N-（哌啶-1-基）-5-（4-碘苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺（AM 251）的抗病毒作用。还测量了对参与脂质代谢的基因表达的影响。CB 1短发夹RNA（shRNA）被用来证实这种效应对大麻素受体是特异性的。用AM 251处理强烈抑制HCV RNA（~ 70%）、病毒蛋白（~ 80%）、新病毒颗粒的产生（~ 70%）和病毒感染性（~ 90%）。 正如预期的那样，AM 251降低了促脂肪生成基因（SREBP-1c、FREB、SCD 1和ACC 1）的表达，并刺激了促进脂质氧化的基因（CPT 1和PPARα）。这种作用是由AMP激活的蛋白激酶（AMPK）介导的。与对照组相比，稳定的CB 1敲除HCV感染的细胞显示HCV RNA水平降低。因此，降低CB 1信号传导抑制HCV复制使用药理学抑制剂或CB 1 shRNA。这可能至少部分是由于AMPK激活介导的脂肪生成减少。我们认为，CB 1拮抗剂可能代表了一个全新的一类药物的活性对HCV。
Direct-acting antivirals have significantly improved treatment outcomes in chronic hepatitis C (CHC), but side effects, drug resistance and cost mean that better treatments are still needed. Lipid metabolism is closely linked with hepatitis C virus (HCV) replication, and endocannabinoids are major regulators of lipid homeostasis. The cannabinoid 1 (CB1) receptor mediates these effects in the liver. We have previously shown upregulation of CB1 receptors in the livers of patients with CHC, and in a HCV cell-culture model. Here, we investigated whether CB1 blockade inhibited HCV replication. The antiviral effect of a CB1 antagonist,N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), was examined in HCV strain JFH1 cell-culture and subgenomic replicon models. The effects on the expression of genes involved in lipid metabolism were also measured. CB1 short hairpin RNA (shRNA) was used to confirm that the effects were specific for the cannabinoid receptor. Treatment with AM251 strongly inhibited HCV RNA (~70 %), viral protein (~80 %), the production of new virus particles (~70 %) and virus infectivity (~90 %). As expected, AM251 reduced the expression of pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by AMP-activated protein kinase (AMPK). Stable CB1 knockdown of cells infected with HCV showed reduced levels of HCV RNA compared with controls. Thus, reduced CB1 signalling inhibits HCV replication using either pharmacological inhibitors or CB1 shRNA. This may be due, at least in part, to reduced lipogenesis, mediated by AMPK activation. We suggest that CB1 antagonists may represent an entirely new class of drug with activity against HCV.
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