O'Boyle Donald R, Nower Peter T, Gao Min, Fridell Robert, Wang Chunfu, Hewawasam Piyasena, Lopez Omar, Tu Yong, Meanwell Nicholas A, Belema Makonen, Roberts Susan B, Cockett Mark, Sun Jin-Hua
Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA
Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
Antimicrob Agents Chemother. 2015 Dec 28;60(3):1573-83. doi: 10.1128/AAC.02639-15.
Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potential in vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O'Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245-248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV-NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV-NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.
达卡他韦（DCV）是首个获批的丙型肝炎病毒（HCV）非结构5A复制复合体抑制剂（NS5A RCI），在与靶向其他HCV蛋白的直接作用抗病毒药物（DAA）组成的无干扰素联合方案中具有临床疗效。最近，我们报道了NS5A RCI联合用药在体外增强HCV抑制潜力的情况，定义了一类新的HCV抑制剂，称为NS5A增效剂（J. Sun、D. R. O'Boyle II、R. A. Fridell、D. R. Langley、C. Wang、S. Roberts、P. Nower、B. M. Johnson、F. Moulin、M. J. Nophsker、Y. Wang、M. Liu、K. Rigat、Y. Tu、P. Hewawasam、J. Kadow、N. A. Meanwell、M. Cockett、J. A. Lemm、M. Kramer、M. Belema和M. Gao，《自然》527:245 - 248，2015，doi:10.1038/nature15711）。为了扩展对NS5A增效剂的特性描述，我们测试了DCV与NS5A增效剂针对基因1型至6型复制子以及基因1a、2a和3a型病毒的新联合用药。用DCV、一种NS5A增效剂（NS5A - Syn）或DCV与NS5A - Syn的联合用药处理HCV感染细胞时，抑制动力学具有明显差异。与临床观察到的活性相似，DCV使HCV出现多对数下降，随后因耐药性出现而反弹。DCV - NS5A - Syn联合用药在清除细胞内病毒方面非常高效，这与复制子研究中观察到的趋势一致。用DCV - NS5A - Syn对DCV单药治疗产生的耐药病毒进行再治疗，导致HCV出现多对数下降和反弹，类似于单独使用DCV对野生型（WT）病毒观察到的初始下降和反弹。DCV、NS5A - Syn与一种靶向NS3或NS5B蛋白的DAA组成的三联方案清除了对DCV高度耐药的细胞内病毒。我们的数据支持以下观察结果：DCV与NS5A - Syn的协同相互作用增强了DCV的基因型覆盖范围和耐药屏障，为联合治疗提供了另一种DAA选择，并为探索NS5A功能提供了工具。
