铂基抗癌药物与蛋白质配位键相互作用质谱研究新进展

顺铂及其类似物广泛应用于肿瘤的临床治疗，静脉注射顺铂后，药物通过血液传输进入细胞并最终到达细胞核作用于DNA，这一过程中，大部分的铂与血液及细胞中的蛋白质通过配位键结合，对药物的运输、代谢、累积分布和毒副作用及其生物利用度等起着决定性作用。因此，研究铂类药物与蛋白质的结合行为具有重要意义。质谱作为一种高效的蛋白质分析技术，具有灵敏度高、通量大、耗样量小、精度高等优势，在铂类药物与蛋白质相互作用研究领域发挥着重要作用。本文从Pt(Ⅱ)配合物的配位化学原理出发，阐明铂药发挥抗癌作用的可能机制。同时，着重总结、评述不同类型质谱分析方法探索铂-蛋白质配位相互作用的最新进展，归纳铂类药物在体内可能通过配位键结合的氨基酸侧链和对应的蛋白质。以顺铂为代表的Pt(Ⅱ)金属抗癌药物，最容易结合含有S供体的半胱氨酸、甲硫氨酸和含有咪唑基团的组氨酸等氨基酸侧链。同时，酪氨酸、丝氨酸、苏氨酸、谷氨酸和天冬氨酸等含羟基或羧基侧链的氨基酸也能与Pt(Ⅱ)结合。由于巯基或咪唑侧链可能处于很多蛋白质的重要活性位点或金属结合域，因此，铂类化合物的结合可能直接导致这些蛋白质的活性下降，从而对细胞内的生物过程产生复杂而深远的影响，加强或降低铂类抗癌药物的活性，或产生毒副作用和耐药性。因此，深入研究铂类药物与蛋白质的相互作用，将进一步加深对铂类抗癌药物代谢途径和毒性机制的认识，有助于设计合成更低毒、高效的金属类抗癌药物。

Update Advances in Investigation of Coordinating Interactions between Platinum-Based Anticancer Drugs and Proteins by Mass Spectrometry

Cisplatin and its analogues are widely used in clinical chemotherapy of cancer. After intravenous injection and before reaching to DNA through the cell nucleus, cisplatin may interact with the serum and cellular proteins. Large amount of platinum binds to proteins in the blood and cytoplasm as well as nucleus via coordination bonds. These interactions are critical to the transportation, metabolism, accumulation, side effects and biological availability of the drug. Therefore, it is of great significance to study the binding behavior between platinum drugs and proteins. Mass spectrometry is a powerful technique for protein analysis, being very sensitive, high-throughput, less sample consumption and accurate, and has played an important role in the investigation of interactions between platinum based anticancer drugs and proteins. This article reviewed the coordination chemistry of platinum(Ⅱ) complexes, and demonstrated their possible mechanism of their anti-cancer effects in cells. In particular, this article focused on update advances on the mass spectrometric methodology for investigation of platinum-protein interaction, and summarized the interactions between amino acids/proteins and Pt-based drugs. The platinum(Ⅱ) based anticancer drugs, e.g. cisplatin, tends to bind to S-donors such as Met and Cys. Also His containing imidazole group can bind to Pt(Ⅱ) residues. Meanwhile, O-donors such as Tyr, Ser, Thr, Glu and Asp can interact with Pt(Ⅱ) as well. As the thiol and imidazole groups often occupy the important activity centers or metal binding sites of proteins, the interaction of platinum drugs with these amino acid side chains may directly lead to the loss of activity of these proteins, which may thus influence the cell viability in an extremely complicated way. These influences may enhance or decrease the activity of the drugs, or otherwise, lead to side effects and drug resistance. Nevertheless, these knowledge helps to expand our understanding of the metabolism and toxicity of platinum anticancer drugs, and contributes to the rational design of more low-toxic and efficient metal anticancer drugs.