SKI-1/S1P inhibition: A promising surrogate to statins to block Hepatitis C virus replication
SKI-1/S1P inhibition: A promising surrogate to statins to block Hepatitis C virus replication
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DOI：
10.1016/j.antiviral.2012.05.006
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发表时间：
2012-08-01
影响因子：
7.6
通讯作者：
Labonte, Patrick
中科院分区：
文献类型：
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作者：
Blanchet, Matthieu;Seidah, Nabil G.;Labonte, Patrick
丙型肝炎病毒（HCV）常与脂肪变性、肝硬化和肝细胞癌（HCC）相关。他汀类药物（HMG-CoAR抑制剂）已被证明在体外发挥抗病毒作用，主要是对携带复制子的细胞，但其在体内单独使用的效果仍然存在争议。在临床试验中，当与标准治疗（SOC）联合使用时，它们导致持续病毒学应答者（SVR）的比例增加。在这里，我们研究了SKI-1/S1 P，HMG-CoAR上游的主要脂肪生成途径调节剂，对HCV生命周期的不同阶段的影响。我们比较了最有效的SKI-1/S1 P小分子抑制剂（PF-429242）与一组两种他汀类药物对病毒生命周期不同阶段的HCV抗病毒作用，结果表明SKI-1/S1 P抑制剂比他汀类药物更有效地阻断HCVRNA（JFH-1株）复制（EC 50 = 5.8 μ M）。此外，我们表明PF-429242可以减少Huh 7细胞中的脂滴积累。有趣的是，PF-429242显著降低了感染性颗粒的产生（EC 90 = 4.8 μ M）。他汀类药物无法实现这种抑制作用。因此，SKI-1/S1 P活性对于病毒的产生是必不可少的，其抑制作用应被考虑用于抗病毒药物的开发。(c)出版社：Elsevier B. V.
Hepatitis C virus (HCV) is often associated with steatosis, cirrhosis and hepatocellular carcinoma (HCC). Statins (HMG-CoAR inhibitors) have been shown to exert an antiviral effect in vitro, principally on replicon harboring cells, but the effect of their use alone in vivo remains controversial. In clinical trials, when used in combination with the standards of care (SOC), they led to an increased proportion of sustained virological responder (SVR). Here we investigated the implication of SKI-1/S1P, a master lipogenic pathways regulator upstream of HMG-CoAR, on different steps of HCV life cycle. We compared the HCV antiviral effect of the most potent SKI-1/S1P small molecule inhibitor (PF-429242) with a set of two statins on different steps of the viral life cycle, and showed that SKI-1/S1P inhibitor blocked HCVcc (strain JFH-1) RNA replication (EC50 = 5.8 mu M) more efficiently than statins. Moreover, we showed that PF-429242 could reduce lipid droplets accumulation in Huh7 cells. Interestingly, PF-429242 dramatically reduced infectious particles production (EC90 = 4.8 mu M). Such inhibition could not be achieved with statins. SKI-1/S1P activity is thus essential for viral production and its inhibition should be considered for antiviral drug development. (c) 2012 Published by Elsevier B.V.