The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors.
The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors.
复制标题
DOI：
10.1086/653080
复制
发表时间：
2010-07-01
期刊：
影响因子：
--
通讯作者：
Glenn JS
中科院分区：
文献类型：
--
作者：
Einav S;Sobol HD;Gehrig E;Glenn JS
我们最近发现了一种化合物，盐酸克立咪唑，抑制NS4B的RNA结合和HCV复制。尽管克立咪唑的抗病毒作用显著，但其抗病毒作用中等（对HCV-2a克隆的EC50为8 μ M）。我们假设克立咪唑与其他抗HCV药物联合使用可以增加抗病毒效果，并且还可以减少病毒耐药性的出现。荧光素酶标记的HCV复制试验用于研究包括克立咪唑在内的药物组合的抗病毒作用。使用Loewe相加和布利斯独立模型分析协同作用的数据，并使用HCV集落形成测定进行抗性研究。克雷咪唑的抗病毒作用与HCV蛋白酶抑制剂SCH 503034和VX 950高度协同，没有毒性。相反，克立咪唑与干扰素、利巴韦林或核苷（NM 283）和非核苷（HCV 796）HCV聚合酶抑制剂的组合是相加的。此外，克立咪唑与SCH 503034的组合与单独使用任一种药物的治疗相比降低了耐药突变体的频率。最后，没有观察到SCH 503034抗性突变体对克立咪唑的交叉抗性（反之亦然）。克雷咪唑可以与蛋白酶抑制剂类产生高水平的协同作用。在未来的抗HCV鸡尾酒中加入克立咪唑可以代表增加当前病毒学应答率的有吸引力的范例。
We recently identified a compound, clemizole hydrochloride, that inhibits NS4B’s RNA binding and HCV replication. Although significant, clemizole’s antiviral effect is moderate (8μM EC50 against an HCV-2a clone). We hypothesized that combination of clemizole with other anti-HCV agents can increase the antiviral effect over that achieved with each drug alone, and could also decrease emergence of viral resistance. Luciferase reporter-linked HCV replication assays were used to study the antiviral effects of drug combinations including clemizole. Data was analyzed using Loewe additivity and Bliss independence models for synergy, and resistance studies were performed using HCV colony formation assays. Clemizole’s antiviral effect was highly synergistic with the HCV protease inhibitors SCH503034 and VX950, without toxicity. In contrast, combinations of clemizole with either interferon, ribavirin, or the nucleoside (NM283) and non-nucleoside (HCV796) HCV polymerase inhibitors were additive. Furthermore, combination of clemizole with SCH503034 decreased the frequency of resistant mutants compared to treatment with either drug alone. Finally, no cross resistance to clemizole of SCH503034-resistant mutants (or vice versa) was observed. Clemizole can yield high level synergy with the protease inhibitors class. Inclusion of clemizole in future anti-HCV cocktails can represent an attractive paradigm for increasing current virologic response rates.
登录
查看更多内容
影响因子：
46.9
作者：
Einav, Shirit;Gerber, Doron;Bryson, Paul D.;Sklan, Ella H.;Elazar, Menashe;Maerkl, Sebastian J.;Glenn, Jeffrey S.;Quake, Stephen R.
通讯作者：
Quake, Stephen R.
影响因子：
4.9
作者：
Malcolm, BA;Liu, R;Njoroge, FG
通讯作者：
Njoroge, FG
DOI：
10.1002/jps.3030490107
发表时间：
1960-01-01
期刊：
JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION
影响因子：
--
作者：
FINKELSTEIN, M;KROMER, CM;DELAHUNT, CS
通讯作者：
DELAHUNT, CS
影响因子：
4.9
作者：
Delaney, WE;Yang, HL;Xiong, S
通讯作者：
Xiong, S
影响因子：
4.9
作者：
Mathy, Joanna E.;Ma, Sue;Lin, Kai
通讯作者：
Lin, Kai