化学蛋白质组学研究铂类抗癌药物在复杂生物体系中的结合蛋白

Platinum chemotherapeutics, such as cisplatin, are widely used in the treatment of tumors in clinic. Studies have shown that the binding of proteins with these drugs is closely related to their mechanism of action. Existing proteomic methods have identified a few high-abundance binding proteins of cisplatin in serum. However, they can’t systematically compare the binding preferences of different platinum anticancer drugs with proteins in complex systems. This project takes full advantage of the high affinity of platinum anticancer drugs with cysteine. With the help of alkynyl benziodoxolone azide probe which has good reactivity and selectivity to intracellular protein cysteine, a chemical proteomic method is established based on competitive ABPP and TMT labeling technology, and proteome covalently binding with platinum drugs through cysteine are isolated and identified from complex biological systems. Then, chemical biology and bioinformatics methods are used to explore the influence of cysteine binding on the activity and function of key proteins, and to explain the mechanism of its activity, drug resistance and toxic side effects. This study is expected to elucidate the affinity of different platinum anticancer drugs with protein cysteine in complex systems, and provide scientific basis for the structure-activity relationship and rational design of platinum anticancer drugs.

以顺铂为代表的铂类化疗药物在临床上广泛用于治疗肿瘤，研究表明体内蛋白质和该类药物的结合与其作用机理密切相关。现有的蛋白质组学方法已鉴定出顺铂在血清中的少数高丰度结合蛋白，然而无法系统性比较不同铂类抗癌药物与复杂体系中蛋白质结合的偏好性。本项目充分利用临床上广泛使用的铂类抗癌药物对半胱氨酸具有高亲和力的特点，借助对细胞内蛋白质半胱氨酸具有很好的反应活性和选择性的苯碘酰炔基叠氮探针，建立基于竞争性ABPP技术和TMT标记技术的化学蛋白质组学方法，从复杂生物体系中分离、鉴定通过半胱氨酸与铂类药物共价结合的蛋白质组，然后运用化学生物学和生物信息学方法探究药物与半胱氨酸结合对关键蛋白活性和功能的影响，解释其活性、耐药性和毒副作用产生的机制。该研究预期阐明不同铂类抗癌药物与复杂体系中蛋白质半胱氨酸的亲和性，为铂类抗癌药物的构效关系和合理设计提供科学依据。

以顺铂为代表的铂类化疗药物在临床上广泛用于治疗肿瘤，研究表明体内蛋白质和该类药物的结合与其作用机理密切相关。本项目充分利用临床上广泛使用的铂类抗癌药物对半胱氨酸具有高亲和力的特点，借助对细胞内蛋白质半胱氨酸具有很好的反应活性和选择性的探针，建立了基于竞争性ABPP技术和同位素标记技术的化学蛋白质组学方法，从细胞和血液中分离、鉴定出通过半胱氨酸与铂类药物共价结合的蛋白质组，并运用生物信息学方法探究药物与半胱氨酸结合对蛋白活性和功能的影响，解释其活性、耐药性和毒副作用产生的机制。该研究阐明了不同铂类抗癌药物与复杂体系中蛋白质半胱氨酸的亲和性，为铂类抗癌药物的构效关系和合理设计提供了科学依据。