Wright M H, Sieber S A
Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany.
Nat Prod Rep. 2016 May 4;33(5):681-708. doi: 10.1039/c6np00001k.
Covering: 2010 up to 2016Deconvoluting the mode of action of natural products and drugs remains one of the biggest challenges in chemistry and biology today. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to understand protein function. In the context of natural products, chemical proteomics can be used to identify the protein binding partners or targets of small molecules in live cells. Here, we highlight recent examples of chemical probes based on natural products and their application for target identification. The review focuses on probes that can be covalently linked to their target proteins (either via intrinsic chemical reactivity or via the introduction of photocrosslinkers), and can be applied "in situ" - in living systems rather than cell lysates. We also focus here on strategies that employ a click reaction, the copper-catalysed azide-alkyne cycloaddition reaction (CuAAC), to allow minimal functionalisation of natural product scaffolds with an alkyne or azide tag. We also discuss 'competitive mode' approaches that screen for natural products that compete with a well-characterised chemical probe for binding to a particular set of protein targets. Fuelled by advances in mass spectrometry instrumentation and bioinformatics, many modern strategies are now embracing quantitative proteomics to help define the true interacting partners of probes, and we highlight the opportunities this rapidly evolving technology provides in chemical proteomics. Finally, some of the limitations and challenges of chemical proteomics approaches are discussed.
2010年至2016年
解析天然产物和药物的作用模式仍然是当今化学和生物学领域面临的最大挑战之一。化学蛋白质组学是化学生物学中一个不断发展的领域，旨在设计小分子探针以了解蛋白质功能。在天然产物的背景下，化学蛋白质组学可用于识别活细胞中小分子的蛋白质结合伙伴或靶点。在此，我们重点介绍基于天然产物的化学探针的最新实例及其在靶点识别中的应用。本综述聚焦于能够与其靶蛋白共价连接（通过内在化学反应性或通过引入光交联剂）且可在“原位”——在生物系统而非细胞裂解物中应用的探针。我们还在此重点介绍采用点击反应（铜催化的叠氮化物-炔烃环加成反应（CuAAC））的策略，以使天然产物支架用炔烃或叠氮化物标签进行最小程度的功能化修饰。我们还讨论了“竞争模式”方法，即筛选与特征明确的化学探针竞争结合特定一组蛋白质靶点的天然产物。受质谱仪器和生物信息学进展的推动，许多现代策略现在都采用定量蛋白质组学来帮助确定探针的真正相互作用伙伴，我们强调了这一快速发展的技术在化学蛋白质组学中提供的机遇。最后，讨论了化学蛋白质组学方法的一些局限性和挑战。
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