美国哈佛医学院Steven P. Gygi课题组的最新研究揭示了药物作用机制的蛋白质组全图谱。该研究于2023年1月2日发表于国际学术期刊《自然—生物技术》杂志。
研究人员研发了一种基于96孔板的高通量筛选策略，对蛋白质组学定量，并在人类癌细胞系中分析了875种化合物的功效，近乎覆盖了整个蛋白质组。通过检测24小时内的蛋白质组变化，研究人员揭示了配体诱导的蛋白质表达变化，发现化合物可调控其蛋白质靶点同时揭示了其识别假定二氢叶酸还原酶和 tankyrase抑制剂的规律。使用蛋白质-蛋白质和化合物-化合物相关网络来揭示几种化合物的作用机制，包括肾上腺素能受体拮抗剂JP1302，研究发现其破坏FACT复合物并降解组蛋白H1。
通过对具有广泛化学空间结构以及靶标重叠化合物进行分析，研究人员将化合物结构与作用机制联系起来，并揭示了化合物库中分子的脱靶药理学。
据悉，确定细胞对药物的反应对于理解小分子扰动剂的作用机制至关重要。
附：英文原文
Title: A proteome-wide atlas of drug mechanism of action
Author: Mitchell, Dylan C., Kuljanin, Miljan, Li, Jiaming, Van Vranken, Jonathan G., Bulloch, Nathan, Schweppe, Devin K., Huttlin, Edward L., Gygi, Steven P.
Issue&Volume: 2023-01-02
Abstract: Defining the cellular response to pharmacological agents is critical for understanding the mechanism of action of small molecule perturbagens. Here, we developed a 96-well-plate-based high-throughput screening infrastructure for quantitative proteomics and profiled 875 compounds in a human cancer cell line with near-comprehensive proteome coverage. Examining the 24-h proteome changes revealed ligand-induced changes in protein expression and uncovered rules by which compounds regulate their protein targets while identifying putative dihydrofolate reductase and tankyrase inhibitors. We used protein–protein and compound–compound correlation networks to uncover mechanisms of action for several compounds, including the adrenergic receptor antagonist JP1302, which we show disrupts the FACT complex and degrades histone H1. By profiling many compounds with overlapping targets covering a broad chemical space, we linked compound structure to mechanisms of action and highlighted off-target polypharmacology for molecules within the library.
DOI: 10.1038/s41587-022-01539-0
Source: https://www.nature.com/articles/s41587-022-01539-0
Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex
本期文章：《自然—生物技术》：Online/在线发表
