Medivir AB, PO Box 1086, Lunastigen 7, Huddinge, SE-141 22, Sweden.
Virus Res. 2012 Dec;170(1-2):1-14. doi: 10.1016/j.virusres.2012.09.007. Epub 2012 Sep 23.
Hepatitis C virus (HCV) is a modern-day pandemic; 2-3% of the world's population are thought to be infected with the virus and are subsequently at risk of developing end-stage liver diseases. The traditional standard of care (SOC) for HCV-infected patients has been limited to a regimen of pegylated-interferon alpha (pegIFN) and ribavirin; displaying low cure rates in a majority of patients and severe side effects. However, in 2011 the first direct-acting antivirals (DAA) were licensed to treat HCV-infected patients in combination with SOC, which served to elevate treatment response rates. The HCV drug development pipeline is currently populated with many additional and improved DAAs; primarily molecules that target the virus-encoded protease or polymerase enzymes. These molecules are being evaluated both in combination with the traditional SOC and together with other DAAs as all-oral pegIFN-free regimens with the ultimate goal of developing multiple DAA-containing HCV therapies that do not rely on an pegIFN backbone. A recent addition to the arsenal of HCV inhibitors in development is represented by an entirely new DAA class; molecules that target the HCV-encoded non-enzymatic NS5A protein. NS5A is essential for HCV propagation and, although its actual functions are largely unknown, it is likely a key regulator of viral genome replication and virion assembly. The protein is exquisitely sensitive to small molecule-mediated inhibition; NS5A-targeting molecules are probably the most potent antiviral molecules ever discovered and exhibit a number of other attractive drug-like properties, including activity against many HCV genotypes/subtypes and once-daily dosing potential. Although their mechanism of action is unclear, NS5A-targeting molecules are already proving their utility in clinical evaluation; particularly as components of pegIFN-sparring DAA combination regimens. This review will aim to amalgamate our current understanding and knowledge of NS5A-targeting molecules; their discovery, properties, applications, and insight into their future impact as components of all-oral pegIFN-free DAA combination therapies to combat HCV infection.
丙型肝炎病毒 (HCV) 是一种现代的大流行病；据认为，世界上有 2-3%的人口感染了该病毒，因此有发展为终末期肝病的风险。感染 HCV 的患者的传统标准治疗 (SOC) 一直限于聚乙二醇干扰素 alpha (pegIFN) 和利巴韦林的方案；在大多数患者中治愈率低，且副作用严重。然而，2011 年，第一批直接作用抗病毒药物 (DAA) 被批准与 SOC 联合用于治疗 HCV 感染患者，这提高了治疗反应率。目前，HCV 药物研发管道中还有许多其他改进的 DAA；主要是针对病毒编码的蛋白酶或聚合酶的分子。这些分子正在与传统 SOC 联合以及与其他 DAA 联合进行评估，作为无 pegIFN 的全口服方案，最终目标是开发多种不依赖 pegIFN 骨干的包含 DAA 的 HCV 治疗方法。最近，HCV 抑制剂研发领域增加了一种全新的 DAA 类别；针对 HCV 编码的非酶 NS5A 蛋白的分子。NS5A 对 HCV 的复制至关重要，尽管其实际功能尚不清楚，但它可能是病毒基因组复制和病毒体组装的关键调节剂。该蛋白对小分子介导的抑制非常敏感；NS5A 靶向分子可能是有史以来发现的最有效的抗病毒分子，并且具有许多其他有吸引力的药物样特性，包括对许多 HCV 基因型/亚型的活性和每日一次给药的潜力。尽管其作用机制尚不清楚，但 NS5A 靶向分子在临床评估中已经证明了它们的实用性；特别是作为 pegIFN 节省 DAA 联合方案的组成部分。这篇综述旨在综合我们目前对 NS5A 靶向分子的理解和认识；它们的发现、性质、应用以及作为无 pegIFN 的全口服 DAA 联合疗法成分对抗 HCV 感染的未来影响的见解。
