金配合物靶向调控细胞内铜离子转运过程的分子机制和结构基础研究

Malignant tumor is one of the major diseases threatening human life and health, the research and development of anti-tumor drugs still has a long way to go. Copper is an essential trace metal elements, and in humans disorder in copper metabolism can lead to many diseases, including the tumor proliferation. Recently research indicated the way that using designed small molecules which can targeted inhibit the human copper-trafficking proteins and control the copper concentration in tumor cells will be the new direction to develop anticancer drugs. So in this proposal, we will study the interactions between the human copper chaperons Atox1/CCS and gold coordination complexes, and try to reveal the molecular mechanism and structural basis. Then, supplemented by the computational stimulation and design, we attempt to synthesize a series of new gold coordination complexes which can highly selective binding with human copper chaperones. We will also test the cancer cell inhibition activity of these new gold coordination complexes in vivo. This study will provide a guidance to design, imitation and synthesize new metal anticancer drugs in the future.

恶性肿瘤是威胁人类生命健康的主要疾病之一，抗肿瘤药物的研发工作任重而道远。铜是人体必需的微量金属元素，铜离子水平的紊乱会导致多种疾病, 包括肿瘤的生长增殖。最新研究表明，通过开发筛选小分子化合物靶向抑制细胞内铜离子调控和转运通路，进而调节恶性肿瘤细胞内铜离子浓度的方法，很可能将成为研究新型抗肿瘤药物的新途径。因此，本项目希望通过在体外研究人体细胞内铜离子转运蛋白Atox1、CCS与Au（I）及常见Au（I）配合物之间的相互作用关系，揭示其中的分子机制和结构基础；并在此基础上，辅以计算机模拟技术和化学生物学手段，尝试合成获得一批能够高效、特异、稳定结合铜离子转运蛋白，并具有在体内靶向抑制肿瘤细胞增殖活性的新型Au（I）配合物，这将对今后在实验室中设计、模仿和制备新型金属抗癌药物提供指导作用。

本项目从人源铜离子转运蛋白异源重组表达及其与金属配合物的化学生物学研究、人源铜离子转运蛋白Atox1与金属配合物的复合物晶体结构解析及新型金属配合物的设计、筛选、合成与活性测试三个层面入手，系统性地对金属配合物靶向调控细胞内铜离子转运过程的分子机制和结构基础进行了研究，获得了一系列铜离子蛋白与金属离子的复合物晶体结构数据，这些研究成果将为通过靶向抑制铜离子调控和转运通路，研发新型抗肿瘤药物提供新策略。