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Secretome-Based Screening in Target Discovery

机译：目标发现中基于Secretome的筛选

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摘要

Secreted proteins and their cognate plasma membrane receptors regulate human physiology by transducing signals from the extracellular environment into cells resulting in different cellular phenotypes. Systematic use of secretome proteins in assays enables discovery of novel biology and signaling pathways. Several secretome-based phenotypic screening platforms have been described in the literature and shown to facilitate target identification in drug discovery. In this review, we summarize the current status of secretome-based screening. This includes annotation, production, quality control, and sample management of secretome libraries, as well as how secretome libraries have been applied to discover novel target biology using different disease-relevant cell-based assays. A workflow for secretome-based screening is shared based on the AstraZeneca experience. The secretome library offers several advantages compared with other libraries used for target discovery: (1) screening using a secretome library directly identifies the active protein and, in many cases, its cognate receptor, enabling a rapid understanding of the disease pathway and subsequent formation of target hypotheses for drug discovery; (2) the secretome library covers significant areas of biological signaling space, although the size of this library is small; (3) secretome proteins can be added directly to cells without additional manipulation. These factors make the secretome library ideal for testing in physiologically relevant cell types, and therefore it represents an attractive approach to phenotypic target discovery.
机译：分泌的蛋白质及其同源质膜受体通过将信号从细胞外环境传导到细胞中，从而导致不同的细胞表型，从而调节人类的生理机能。在测定中系统地使用分泌组蛋白可以发现新的生物学和信号通路。文献中已经描述了几种基于分泌组的表型筛选平台，这些平台可以促进药物发现中的靶标鉴定。在这篇综述中，我们总结了基于分泌组的筛选的当前状态。这包括注释，生产，质量控制和分泌组文库的样品管理，以及如何使用不同疾病相关的基于细胞的检测方法将分泌组文库应用于发现新的靶标生物学。基于阿斯利康的经验，共享了基于分泌组的筛选工作流程。与用于靶标发现的其他文库相比，secretome文库具有几个优势：（1）使用secretome文库进行筛选可以直接识别活性蛋白，在许多情况下还可以识别其同源受体，从而可以快速了解疾病途径和随后形成针对药物发现的目标假设; （2）尽管该文库的规模很小，但其组覆盖了生物信号空间的重要区域; （3）分泌组蛋白可以直接添加到细胞中，而无需其他操作。这些因素使Secretome文库非常适合在生理相关细胞类型中进行测试，因此它代表了表型靶标发现的一种有吸引力的方法。

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