Identification of Small Molecules that Interfere with H1N1 Influenza A Viral Replication
Identification of Small Molecules that Interfere with H1N1 Influenza A Viral Replication
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DOI：
10.1002/cmdc.201200453
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发表时间：
2012-12-01
期刊：
影响因子：
3.4
通讯作者：
Pellecchia, Maurizio
中科院分区：
文献类型：
--
作者：
Bottini, Angel;De, Surya K.;Pellecchia, Maurizio
甲型流感病毒的成功复制需要病毒蛋白和宿主细胞因子。在这项研究中，我们使用了一种细胞分析来筛选能够干扰任何这种必要的病毒或细胞成分的小分子。我们使用了一种已建立的报告基因测定法，通过监测共表达荧光素酶的活性来评估流感病毒的复制。我们筛选了一个多样化的化合物库，从而鉴定出化合物7，它抑制了一个新的但难以捉摸的靶标。定量实时PCR研究证实了化合物7在病毒复制测定中的剂量依赖性抑制活性。此外，我们显示化合物7在体内小鼠模型中有效地挽救高剂量流感感染。随着奥司他韦耐药流感病毒株的出现，化合物7可以作为一种新的和潜在的合适的支架进一步研究，用于开发作用于新靶点的抗流感药物。
Successful replication of the influenza A virus requires both viral proteins and host cellular factors. In this study we used a cellular assay to screen for small molecules capable of interfering with any of such necessary viral or cellular components. We used an established reporter assay to assess influenza viral replication by monitoring the activity of co-expressed luciferase. We screened a diverse chemical compound library, resulting in the identification of compound 7, which inhibits a novel yet elusive target. Quantitative real-time PCR studies confirmed the dose-dependent inhibitory activity of compound 7 in a viral replication assay. Furthermore, we showed that compound 7 is effective in rescuing high-dose influenza infection in an in vivo mouse model. As oseltamivir-resistant influenza strains emerge, compound 7 could be further investigated as a new and potentially suitable scaffold for the development of anti-influenza agents that act on novel targets.