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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes
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Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes

机译：丙型肝炎病毒NS5B聚合酶抑制剂BMS-791325对所有主要基因型的效力和耐药性分析

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摘要

BMS-791325 is a hepatitisCvirus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependentRNApolymerase. BMS- 791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC50],<10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A.Lemmet al., Antimicrob. Agents Chemother. 58:3485-3495, 2014, doi:http://dx.doi.org/10.1128/AAC.02495-13). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC50s similar to that for GT1 while a third patient clone was-10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS- 791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in-21% of sequences in the EuropeanHCVdatabase. The results from this report suggest that BMS-791325 is a candidate for combination treatment ofHCVGT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.
机译：BMS-791325是与NS5B RNA依赖性RNA聚合酶的拇指结构域结合的丙型肝炎病毒（HCV）抑制剂。 BMS-791325在基因型1（GT1）中具有良好的特征，并且对含有GT3a，-4a和-5a患者NS5B序列的杂合复制子表现出良好的抑制活性（50％有效浓度[EC50]，<10 nM），而对GT2的效价强（JALemmet等人，Antimicrob.Agents Chemother.58：3485-3495，2014，doi：http：//dx.doi.org/10.1128/AAC.02495-13）。 BMS-791325对GT6a杂合复制子的效力更具可变性，三个杂合克隆中的两个具有与GT1相似的EC50，而第三个患者克隆对BMS-791325的敏感性低10倍。为了表征BMS-791325超出GT1的电阻曲线，在GT1a和-3a到-6a上进行了固化研究，结果表明GT1a的电阻势垒比BMS-791325高，而GT6a的电阻势垒最低。在不同浓度的BMS-791325中选择GT3到-6个NS5B嵌合复制子细胞后，NS5B拇指域中的残基494和495发生了置换，从而赋予了对BMS-791325的不同水平的抗性，但仍易受NS5A或NS3蛋白酶抑制剂的影响。此外，我们证明BMS-791325对一名GT6a患者的效力降低是由于在欧洲HCV数据库中21％的序列中存在A494多态性。该报告的结果表明，BMS-791325是HCVGT3与-6种慢性感染联合治疗的候选药物，确定的耐药性将为将来的临床开发提供有用的信息。

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