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Characterization of aurintricarboxylic acid as a potent hepatitis C virus replicase inhibitor

机译：渗碳羧酸的表征作为有效的丙型肝炎病毒复制酶抑制剂

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Background: Hepatitis C virus (HCV) NS5B is an essential component of the viral replication machinery and an important target for antiviral intervention. Aurintricarboxylic acid (ATA), a broad-spectrum antiviral agent, was evaluated and characterized for its anti-NS5B activity in vitro and in HCV replicon cells.Methods: Recombinant NS5B, HCV replicase and Huh-7 cells harbouring the subgenomic HCV replicon of genotype 1b were employed for biochemical and mechanistic investigations.Results: Analysis of ATA activity in vitro yielded equipo-tent inhibition of recombinant NS5B and HCV replicase in the submicromolar range (50% inhibition concentration [IC_(50)] approximately 150 nM). Biochemical and mechanistic studies revealed a bimodal mechanism of ATA inhibition with characteristics of pyrophosphate mimics and non-nucleoside inhibitors. Molecular modelling andcompetition displacement studies were consistent with these parameters, suggesting that ATA might bind to the benzothiadiazine allosteric pocket 3 of NS5B or at its catalytic centre. Kinetic studies revealed a mixed mode of ATA inhibition with respect to both RNA and UTP substrates. Under single-cycle assay conditions, ATA inhibited HCV NS5B initiation and elongation from pre-bound RNA, but with >fivefold decreased potency compared with continuous polymerization conditions. The IC_(50) value of ATA for the native replicase complex was 145 nM. In HCV replicon cells, ATA treatment ablated HCV RNA replication (50% effective concentration =75 nM) with concomitant decrease in NS5B expression and no apparent cytotoxic effects. Conclusions: This study identified ATA as a potent anti-NS5B inhibitor and suggests that its unique mode of action might be exploited for structural refinement and development of novel anti-NS5B agents.
机译：背景：丙型肝炎病毒（HCV）NS5B是病毒复制机械的重要组成部分和抗病毒干预的重要目标。评估菌氨羧酸（ATA），广谱抗病毒剂，其在体外和HCV复制子细胞中进行抗NS5B活性。方法：重组NS5B，HCV复制酶和HUH-7细胞，含有基因型的亚基组织HCV复制子使用1B用于生化和机械研究。结果：在亚微粒范围（50％抑制浓度[IC_（50）]约150nm的50％抑制浓度[IC_（50）]约150nm）中，对体外的ATA活性分析。生物化学和机械研究揭示了ATA抑制与焦磷酸盐模拟物和非核苷抑制剂特征的双峰机制。分子造型和竞争性位移研究与这些参数一致，表明ATA可能与NS5B或其催化中心的苯并噻嗪叠胶袋3结合。动力学研究揭示了关于RNA和UTP底物的ATA抑制的混合模式。在单循环测定条件下，ATA抑制HCV NS5B引发和来自预结合的RNA的伸长，但与连续聚合条件相比，>五倍降低效力。本机复制酶复合体的ATA的IC_（50）值为145nm。在HCV复制子细胞中，ATA治疗烧蚀HCV RNA复制（50％有效浓度= 75nm），NS5B表达的伴随地减少，没有表观细胞毒性作用。结论：本研究确定ATA作为有效的抗NS5B抑制剂，并表明其独特的作用方式可能是用于结构性细化和新型抗NS5B药剂的发展。

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