Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay.
Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay.
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DOI：
10.1016/j.antiviral.2015.10.018
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发表时间：
2015-12
影响因子：
7.6
通讯作者：
Liang TJ
中科院分区：
文献类型：
--
作者：
Hu Z;Hu X;He S;Yim HJ;Xiao J;Swaroop M;Tanega C;Zhang YQ;Yi G;Kao CC;Marugan J;Ferrer M;Zheng W;Southall N;Liang TJ
丙型肝炎病毒(丙型肝炎病毒)对世界构成重大的健康威胁。近年来，针对丙型肝炎病毒的直接作用抗病毒药物(DAA)的发展，与干扰素治疗相比，显著提高了丙型肝炎病毒的应答率，并减少了副作用。尽管取得了这一治疗进展，但由于目前治疗方案的各种局限性，仍有必要开发针对丙型肝炎病毒生命周期不同阶段的新抑制剂。在这项研究中，我们使用我们之前开发的基于细胞的丙型肝炎病毒感染分析方法，对包含约350,000种化学物质的分子库小分子存储库(MLSMR)进行了定量的高通量筛选，以寻找新型的丙型肝炎病毒抑制剂。经过确认和结构聚类分析，我们从最初的~3,000个分子中缩小到158个化合物，为进一步的结构和功能分析显示了抑制活性。我们能够将这些化合物中的大多数分配到丙型肝炎病毒生命周期的特定阶段(S)。其中三个是NS3/4A蛋白水解酶的直接抑制物。大多数化合物似乎作用于丙型肝炎病毒生命周期中的新靶点。四个具有新颖结构和良好类药物性质的化合物，三个靶向丙型肝炎病毒进入，一个靶向丙型肝炎病毒组装/分泌，被提出作为先导化合物进一步开发。这些化合物代表了不同的化学类型，是进一步优化的潜在先导化合物，并可能为开发抗丙型肝炎病毒感染的新疗法提供有前途的候选药物。此外，它们还代表了探索丙型肝炎病毒与细胞之间复杂相互作用的新型分子探针。
Hepatitis C virus (HCV) poses a major health threat to the world. The recent development of direct-acting antivirals (DAAs) against HCV has markedly improved the response rate of HCV and reduced the side effects in comparison to the interferon-based therapy. Despite this therapeutic advance, there is still a need to develop new inhibitors that target different stages of the HCV life cycle because of various limitations of the current regimens. In this study, we performed a quantitative high-throughput screening of the Molecular Libraries Small Molecule Repository (MLSMR) of ~ 350,000 chemicals for novel HCV inhibitors using our previously developed cell-based HCV infection assay. Following confirmation and structural clustering analysis, we narrowed down to 158 compounds from the initial ~ 3,000 molecules that showed inhibitory activity for further structural and functional analyses. We were able to assign the majority of these compounds to specific stage(s) in the HCV life cycle. Three of them are direct inhibitors of NS3/4A protease. Most of the compounds appear to act on novel targets in HCV life cycle. Four compounds with novel structure and excellent drug-like properties, three targeting HCV entry and one targeting HCV assembly/secretion, were advanced for further development as lead hits. These compounds represent diverse chemotypes that are potential lead compounds for further optimization and may offer promising candidates for the development of novel therapeutics against HCV infection. In addition, they represent novel molecular probes to explore the complex interactions between HCV and the cells.