中山大学谭彩萍等取得重要工作进展。他们通过亲和蛋白质谱技术鉴定出线粒体ATP合酶作为Ru-多吡啶-β-咔啉配合物的细胞靶点。相关研究成果2024年7月5日在线发表于《国家科学评论》杂志上。

据介绍，钌多吡啶配合物是很有前景的抗癌候选物，但其细胞靶点尚未确定，这限制了其临床应用。

研究人员设计了一系列含有生物活性β-咔啉衍生物作为配体的Ru（II）多吡啶配合物进行抗癌评估，其中Ru5具有合适的亲脂性、高水溶性、相对较高的抗癌活性和癌症细胞选择性。然后使用相应的光亲和性探针Ru5a，通过基于光亲和蛋白质图谱来验证ATP合酶是Ru5的重要靶标。Ru5定位于线粒体，损害线粒体功能并诱导线粒体自噬和铁死亡。

线粒体蛋白质组学和RNA测序的联合分析表明，Ru5显著下调氯离子通道蛋白的表达，影响铁死亡和上皮-间质转化相关的基因。最后，研究人员证明了Ru5在体内表现出比顺铂更高的抗癌功效。

总之，这一研究首先使用光亲和性蛋白质组学方法结合多组学方法鉴定了多吡啶钌配合物的分子靶标，这为阐明金属抗癌候选物的抗癌机制提供了一种创新策略。

附：英文原文

Title: Identification of mitochondrial ATP synthase as the cellular target of Ru-polypyridyl-β-carboline complexes by affinity-based protein profiling

Author: Wang, Wen-Jin, Ling, Yu-Yi, Shi, Yin, Wu, Xiao-Wen, Su, Xuxian, Li, Zheng-Qiu, Mao, Zong-Wan, Tan, Cai-Ping

Issue&Volume: 2024-07-05

Abstract: Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified yet, which limits their clinical applications. Herein, we design a series of Ru(II) polypyridyl complexes containing the bioactive β-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. A corresponding photo-clickable probe Ru5a is then used to verify that ATP synthase is an important target of Ru5 by photoaffinity-based protein profiling. Ru5 localizes in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. In all, we firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates

DOI: 10.1093/nsr/nwae234

Source: https://dx.doi.org/10.1093/nsr/nwae234