Different anti-HCV profiles of statins and their potential for combination therapy with interferon
Different anti-HCV profiles of statins and their potential for combination therapy with interferon
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DOI：
10.1002/hep.21232
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发表时间：
2006-07-01
期刊：
影响因子：
13.5
通讯作者：
Kato, Nobuyuki
中科院分区：
文献类型：
--
作者：
Ikeda, Masanori;Abe, Ken-ichi;Kato, Nobuyuki
我们最近开发了一种以荧光素酶为报告基因的基因组长度丙型肝炎病毒 (HCV) RNA 复制系统 (0116)。 OR6 检测系统能够对 HCV RNA 复制进行快速、精确的定量。聚乙二醇干扰素 (IFN) 和利巴韦林联合治疗是慢性 Q 型肝炎的世界标准，但其有效性仅限于约 55% 的患者。需要更新的治疗方法。在本研究中，我们使用 OR6 测定系统来评估 3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶抑制剂（称为他汀类药物）的抗 HCV 活性及其与 IFN-α 联合使用的效果。检查了五种他汀类药物（阿托伐他汀、氟伐他汀、洛伐他汀、普伐他汀和辛伐他汀）的抗 HCV 活性。氟伐他汀表现出最强的抗HCV活性（IC50：0.9μmol/L），而阿托伐他汀和辛伐他汀表现出中等的抑制作用。然而，最近报道的洛伐他汀作为 HCV 复制抑制剂，其抗 HCV 活性最弱。添加甲羟戊酸或香叶基香叶醇可逆转他汀类药物的抗 HCV 活性。然而，令人惊讶的是，普伐他汀没有表现出抗 HCV 活性，尽管它作为 HMG-CoA 还原酶的抑制剂起作用。 IFN和他汀类药物（普伐他汀除外）的组合对HCV RNA复制表现出强烈的抑制作用。氟伐他汀与IFN联合使用也表现出协同抑制作用。总之，他汀类药物，尤其是氟伐他汀，可能与干扰素联合作为新型抗丙肝病毒试剂。
We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (0116) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis Q but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate die anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, called statins, and their effects in combination with IFN-alpha. Five types of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) were examined for their anti-HCV activities. Fluvastatin exhibited the strongest anti-HCV activity (IC50: 0.9 mu mol/ L), whereas atorvastatin and simvastatin showed moderate inhibitory effects. However, lovastatin, reported recently as an inhibitor of HCV replication, was shown to exhibit the weakest anti-HCV activity. The anti-HCV activities of statins were reversed by the addition of mevalonate or geranylgeraniol. Surprisingly, however, pravastatin exhibited no anti-HCV activity, although it worked as an inhibitor for HMG-CoA reductase. The combination of IFN and the statins (except for pravastatin) exhibited strong inhibitory effects on HCV RNA replication. In combination with IFN, fluvastatin also exhibited a synergistic inhibitory effect. In conclusion, statins, especially fluvastatin, could be potentially useful as new anti-HCV reagents in combination with IFN.