Identification of Thieno[3,2-b]Pyrrole Derivatives as Novel Small Molecule Inhibitors of Neurotropic Alphaviruses
Identification of Thieno[3,2-b]Pyrrole Derivatives as Novel Small Molecule Inhibitors of Neurotropic Alphaviruses
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DOI：
10.1086/597275
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发表时间：
2009-04-01
影响因子：
6.4
通讯作者：
Miller, David J.
中科院分区：
文献类型：
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作者：
Peng, Weiping;Peltier, Daniel C.;Miller, David J.
嗜神经性甲病毒，如西方、东方和委内瑞拉马脑炎病毒，在人类中引起严重和潜在致命的中枢神经系统感染，并且是高度优先的潜在生物恐怖主义制剂。目前还没有针对这些致命病原体的广泛可用的疫苗或许可的疗法。为了鉴定潜在的新型抗病毒药物，我们开发了一种基于细胞的检测方法，该方法使用表达荧光素酶报告基因的西方马脑炎病毒复制子，并筛选了51，028种化合物的小分子多样性文库。我们鉴定并验证了噻吩并[3，2-B]吡咯化合物，其半最大抑制浓度为20，并且在培养的神经元细胞中对活病毒具有有效活性。此外，与20个相关化合物的结构-活性关系分析确定了几个增强的活性概况，包括6个亚微摩尔半最大抑制浓度。总之，我们已经确定了一类新的有前途的抑制剂，对有毒的嗜神经甲病毒具有有效的活性。
Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses cause serious and potentially fatal central nervous system infections in humans and are high-priority potential bioterrorism agents. There are currently no widely available vaccines or licensed therapies for these virulent pathogens. To identify potential novel antiviral drugs, we developed a cell-based assay with a western equine encephalitis virus replicon that expresses a luciferase reporter gene and screened a small molecule diversity library of 51,028 compounds. We identified and validated a thieno[3,2-b]pyrrole compound with a half maximal inhibitory concentration of 20, and potent activity against live virus in cultured neuronal cells. Furthermore, a structure-activity relationship analysis with 20 related compounds identified several with enhanced activity profiles, including 6 with submicromolar half maximal inhibitory concentrations. In conclusion, we have identified a novel class of promising inhibitors with potent activity against virulent neurotropic alphaviruses.