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首页> 美国卫生研究院文献>ACS AuthorChoice >Mappingthe Protein Interaction Landscape for FullyFunctionalized Small-Molecule Probes in Human Cells
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Mappingthe Protein Interaction Landscape for FullyFunctionalized Small-Molecule Probes in Human Cells

机译：映射充分发挥蛋白质相互作用的作用人细胞中功能化的小分子探针

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Phenotypic screening provides a means to discover small molecules that perturb cell biological processes. Discerning the proteins and biochemical pathways targeted by screening hits, however, remains technically challenging. We recently described the use of small molecules bearing photoreactive groups and latent affinity handles as fully functionalized probes for integrated phenotypic screening and target identification. The general utility of such probes, or, for that matter, any small-molecule screening library, depends on the scope of their protein interactions in cells, a parameter that remains largely unexplored. Here, we describe the synthesis of an ∼60-member fully functionalized probe library, prepared from Ugi-azide condensation reactions to impart structural diversity and introduce diazirine and alkyne functionalities for target capture and enrichment, respectively. In-depth mass spectrometry-based analysis revealed a diverse array of probe targets in human cells, including enzymes, channels, adaptor and scaffolding proteins, and proteins of uncharacterized function. For many of these proteins,ligands have not yet been described. Most of the probe–proteininteractions showed well-defined structure–activity relationshipsacross the probe library and were blocked by small-molecule competitorsin cells. These findings indicate that fully functionalized smallmolecules canvas diverse segments of the human proteome and hold promiseas pharmacological probes of cell biology.
机译：表型筛选提供了一种发现扰动细胞生物学过程的小分子的方法。然而，识别筛选命中所靶向的蛋白质和生化途径在技术上仍然具有挑战性。我们最近描述了使用带有光反应性基团和潜在亲和力的小分子作为用于整合表型筛选和目标识别的功能齐全的探针。这种探针或任何小分子筛选文库的一般用途取决于它们在细胞中蛋白质相互作用的范围，这一参数在很大程度上尚待探索。在这里，我们描述了由Ugi-叠氮化物缩合反应制备的具有60个成员的全功能探针库的合成，以赋予结构多样性并分别引入二嗪和炔烃功能以捕获和富集目标。基于深度质谱的分析揭示了人类细胞中各种各样的探针靶标，包括酶，通道，衔接子和支架蛋白以及功能未知的蛋白。对于许多这些蛋白质，配体尚未被描述。大部分探针蛋白相互作用表现出明确的结构-活性关系整个探针库，被小分子竞争者阻断在细胞中。这些发现表明，功能全面的小型分子覆盖人类蛋白质组的不同部分并抱有希望作为细胞生物学的药理探针。

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