Real-Time NMR-Based Drug Discovery to Identify Inhibitors against Fatty Acid Synthesis in Living Cancer Cells.
Real-Time NMR-Based Drug Discovery to Identify Inhibitors against Fatty Acid Synthesis in Living Cancer Cells.
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DOI：
10.1021/acs.analchem.3c04954
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发表时间：
2024-02
影响因子：
7.4
通讯作者：
Biao Liu;Caixiang Liu;Xin Chai;Xinyu Fan;Tao Huang;Jianhua Zhan;Qinjun Zhu;Danyun Zeng;Zhou Gong;Lichun He;Yunhuang Yang;Xin Zhou;Bin Jiang;Xu Zhang;Maili Liu
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文献类型：
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作者：
Biao Liu;Caixiang Liu;Xin Chai;Xinyu Fan;Tao Huang;Jianhua Zhan;Qinjun Zhu;Danyun Zeng;Zhou Gong;Lichun He;Yunhuang Yang;Xin Zhou;Bin Jiang;Xu Zhang;Maili Liu
脂肪酸代谢异常被认为是肿瘤发生和发展的关键驱动因素。尽管已经开发了许多针对这一途径的抑制剂，但寻找不破坏正常细胞代谢的高特异性药物仍然是一个艰巨的挑战。在本文中，我们介绍了一种新的基于实时核磁共振的药物筛选技术，该技术在活细胞内操作。这项技术提供了一种直接的方法来推测参与特定代谢过程的分子靶点，使其成为基于细胞的药物筛选的有力工具。使用2-13C乙酸酯作为示踪剂，结合3D细胞团和生物反应器系统，我们的方法能够实时检测针对活细胞内脂肪酸新陈代谢的抑制剂。结果，我们成功地展示了这种方法在发现特定针对脂肪酸代谢的中药方面的初步应用。由于草药化合物的复杂性质和多个靶点的存在，阐明草药背后的机制仍然具有挑战性。值得注意的是，我们的发现证明了P.cos对细胞内脂肪酸合成的显著抑制作用，说明了这种方法在分析脂肪酸代谢事件和识别在细胞水平选择性抑制脂肪酸合成的候选药物方面的潜力。此外，这种系统的方法代表了一种发现草药复杂效果的有价值的策略。
Abnormal fatty acid metabolism is recognized as a key driver of tumor development and progression. Although numerous inhibitors have been developed to target this pathway, finding drugs with high specificity that do not disrupt normal cellular metabolism remains a formidable challenge. In this paper, we introduced a novel real-time NMR-based drug screening technique that operates within living cells. This technique provides a direct way to putatively identify molecular targets involved in specific metabolic processes, making it a powerful tool for cell-based drug screening. Using 2-13C acetate as a tracer, combined with 3D cell clusters and a bioreactor system, our approach enables real-time detection of inhibitors that target fatty acid metabolism within living cells. As a result, we successfully demonstrated the initial application of this method in the discovery of traditional Chinese medicines that specifically target fatty acid metabolism. Elucidating the mechanisms behind herbal medicines remains challenging due to the complex nature of their compounds and the presence of multiple targets. Remarkably, our findings demonstrate the significant inhibitory effect of P. cocos on fatty acid synthesis within cells, illustrating the potential of this approach in analyzing fatty acid metabolism events and identifying drug candidates that selectively inhibit fatty acid synthesis at the cellular level. Moreover, this systematic approach represents a valuable strategy for discovering the intricate effects of herbal medicine.