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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Cross-genotypic examination of hepatitis c virus polymerase inhibitors reveals a novel mechanism of action for thumb binders
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Cross-genotypic examination of hepatitis c virus polymerase inhibitors reveals a novel mechanism of action for thumb binders

机译：丙型肝炎病毒聚合酶抑制剂的跨基因型检查揭示了拇指结合剂的新作用机制

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Direct-acting antivirals (DAAs) targeting proteins encoded by the hepatitis C virus (HCV) genome have great potential for the treatment of HCV infections. However, the efficacy of DAAs designed to target genotype 1 (G1) HCV against non-G1 viruses has not been characterized fully. In this study, we investigated the inhibitory activities of nonnucleoside inhibitors (NNIs) against the HCV RNA-dependent RNA polymerase (RdRp). We examined the ability of six NNIs to inhibit G1b, G2a, and G3a subgenomic replicons in cell culture, as well as in vitro transcription by G1b and G3a recombinant RdRps. Of the six G1 NNIs, only the palm II binder nesbuvir demonstrated activity against G1, G2, and G3 HCV, in both replicon and recombinant enzyme models. The thumb I binder JTK-109 also inhibited G1b and G3a replicons and recombinant enzymes but was 41-fold less active against the G2a replicon. The four other NNIs, which included a palm I binder (setrobuvir), two thumb II binders (lomibuvir and filibuvir), and a palm β-hairpin binder (tegobuvir), all showed at least 40-fold decreases in potency against G2a and G3a replicons and the G3a enzyme. This antiviral resistance was largely conferred by naturally occurring amino acid residues in the G2a and G3a RdRps that are associated with G1 resistance. Lomibuvir and filibuvir (thumb II binders) inhibited primer-dependent but not de novo activity of the G1b polymerase. Surprisingly, these compounds instead specifically enhanced the de novo activity at concentrations of >100 nM. These findings highlight a potential differential mode of RdRp inhibition for HCV NNIs, depending on their prospective binding pockets, and also demonstrate a surprising enhancement of de novo activity for thumb RdRp binders. These results also provide a better understanding of the antiviral coverage for these polymerase inhibitors, which will likely be used in future combinational interferon-free therapies.
机译：靶向由丙型肝炎病毒（HCV）基因组编码的蛋白的直接作用抗病毒药（DAA）具有治疗HCV感染的巨大潜力。但是，针对非G1病毒设计的靶向基因型1（G1）HCV的DAA的功效尚未完全表征。在这项研究中，我们调查了非核苷抑制剂（NNIs）对HCV RNA依赖性RNA聚合酶（RdRp）的抑制活性。我们检查了六个NNI在细胞培养中抑制G1b，G2a和G3a亚基因组复制子的能力，以及G1b和G3a重组RdRps的体外转录。在六个G1 NNI中，在复制子和重组酶模型中，只有手掌II结合剂Nesbuvir表现出针对G1，G2和G3 HCV的活性。拇指I结合剂JTK-109也抑制G1b和G3a复制子和重组酶，但对G2a复制子的活性低41倍。其他四个NNI包括棕榈I结合剂（setrobuvir），两种拇指II结合剂（lomibuvir和filibuvir）和棕榈β-发夹结合剂（tegobuvir），它们对G2a和G3a的效力均降低了至少40倍。复制子和G3a酶。这种抗病毒抗药性主要是由G2a和G3a RdRps中与G1抗药性相关的天然氨基酸残基赋予的。 Lomibuvir和filibuvir（thumb II结合物）抑制了引物依赖性的G1b聚合酶活性，但没有。出人意料的是，这些化合物反而在> 100 nM的浓度下特异性增强了从头活性。这些发现强调了HCV NNIs潜在抑制RdRp的差异模式，具体取决于其潜在的结合口袋，并且还证明了拇指RdRp结合剂从头活性的惊人增强。这些结果还提供了对这些聚合酶抑制剂的抗病毒覆盖率的更好理解，这很可能会在未来的无干扰素联合治疗中使用。

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