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Integrated compound profiling screens identify the mitochondrial electron transport Chain as the molecular target of the natural products manassantin, sesquicillin, and arctigenin

机译:集成的化合物分析屏幕可将线粒体电子传输链确定为天然产物马纳森汀,倍半索林和Arctigenin的分子靶标

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Phenotypic compound screens can be used to identify novel targets in signaling pathways and disease processes, but the usefulness of these screens depends on the ability to quickly determine the target and mechanism of action of the molecules identified as hits. One fast route to discovering the mechanism of action of a compound is to profile its properties and to match this profile with those of compounds of known mechanism of action. In this work, the Novartis collection of over 12,000 pure natural products was screened for effects on early zebrafish development. The largest phenotypic class of hits, which caused developmental arrest without necrosis, contained known electron transport chain inhibitors and many compounds of unknown mechanism of action. High-throughput transcriptional profiling revealed that these compounds are mechanistically related to one another. Metabolic and biochemical assays confirmed that all of the molecules that induced developmental arrest without necrosis inhibited the electron transport chain. These experiments demonstrate that the electron transport chain is the target of the natural products manassantin, sesquicillin, and arctigenin. The overlap between the zebrafish and transcriptional profiling screens was not perfect, indicating that multiple profiling screens are necessary to fully characterize molecules of unknown function. Together, zebrafish screening and transcriptional profiling represent sensitive and scalable approaches for identifying bioactive compounds and elucidating their mechanism of action.
机译:表型化合物筛选可用于识别信号传导途径和疾病过程中的新靶标,但这些筛选的有用性取决于快速确定被鉴定为命中分子的靶标和作用机制的能力。发现化合物作用机理的一种快速途径是分析其性质,并使该性质与已知作用机理的化合物相匹配。在这项工作中,对诺华收集的超过12,000种纯天然产品进行了筛选,以了解其对斑马鱼早期发育的影响。最大的表型类别的命中物导致发育停止而不坏死,包含已知的电子传输链抑制剂和许多未知作用机理的化合物。高通量转录谱分析表明,这些化合物在机械上相互关联。代谢和生化分析证实,所有诱导发育停止而无坏死的分子均抑制了电子传输链。这些实验证明,电子传输链是天然产物马纳森汀,倍半索林和arctigenin的目标。斑马鱼和转录谱筛选屏幕之间的重叠并不完美,这表明需要多个谱筛选屏幕来完全表征功能未知的分子。在一起,斑马鱼筛选和转录谱表示鉴定生物活性化合物并阐明其作用机理的灵敏和可扩展的方法。

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