设计合成靶向硫氧还蛋白还原酶的金团簇-多肽复合体及其抑瘤生物效应的研究

The malignant tumor has seriously damaged the health and life of human being, but the traditional platinum-based anticancer drug causes drug resistance and toxic side-effect. The development of novel metallic anticancer drug with different mechanism is urgently desired for malignant tumor therapies now. The thioredoxin reductase (TrxR) plays important roles in cancer cell proliferation, and has become a new target for antitumor. In our recent study, the gold cluster shows the ability to suppress TrxR activity. However, it is still a big challenge for anticancer drug development to realize high effective TrxR activity inhibition and valid tumor therapy. In this program, we will theoretically design and experimentally synthesize a series of targeted gold cluster-peptide complexes to specifically bind the TrxR active center. This could achieve the high effective inhibition of TrxR activity. Moreover, the TrxR activity inhibition efficiency can be additionally improved by the high titer of gold cluster than the normal gold compound. We will disclose the TrxR activity inhibition molecular mechanism of the novel gold cluster based medicine and its antitumor curative effect through the biochemical evaluation, cell experiment and animal antitumor experiment with molecular biology and cell biology technologies. These research results, combining the biological fluorescent image application of gold cluster, will provide the key data and new ideas for the cancer clinical therapy.

恶性肿瘤已严重危害人类生命健康，而传统的抗癌铂类药物会引起强烈抗药性和严重毒副作用，因此开发新颖的、作用方式不同的新型金属类药物，是恶性肿瘤有效治疗迫切需要解决的关键问题。前期研究提示：硫氧还蛋白还原酶TrxR与肿瘤增殖密切相关,是抗癌的重要新靶点。我们初步的研究表明金团簇显示出抑制TrxR活性的潜力。但是如何实现对癌细胞中TrxR酶活性的高效抑制和有效的肿瘤治疗，仍是抗癌药物开发的挑战性难题。本课题以乳腺癌活细胞中TrxR为研究对象，设计制备一系列金团簇-多肽靶向复合体，与TrxR酶活中心特异性结合，进而实现对TrxR酶活性的高效抑制，并利用金团簇的高效价比进一步提高靶向药物对TrxR酶活性抑制的效率。通过生化评价、细胞实验、动物抑瘤实验，运用分子生物学、细胞生物技术手段，揭示新型金团簇药物抑制TrxR活性、抗肿瘤的机制和疗效，结合金团簇在生物成像的应用，为肿瘤治疗临床应用提供崭新思路。

本项目目标是运用分子模拟理论研究手段，结合生化评价、生物实验设计构建系列金团簇-多肽靶向体系，针对包括TrxR在内的重要巯基/硒巯基疾病靶蛋白，实现其生物活性的高效靶向抑制，并揭示其疾病治疗生物效应的分子机制。本项目已顺利完成全部研究内容，已完成：系列典型金团簇-多肽复合体系的结构解析与设计，包括双齿型巯基配体保护金团簇的结构解析与设计、天然谷胱甘肽保护金团簇的结构解析与设计；靶向金团簇与多种巯基/硒巯基膜蛋白、胞浆蛋白结合的生物效应研究，包括靶向金团簇与膜蛋白人类上表皮生长因子受体结合机制研究、靶向金团簇抑制胞浆蛋白谷胱甘肽过氧化物酶-1生物效应研究、及靶向金团簇有效抑制软骨/骨损伤的生物效应研究；应用靶向体系分子设计原则，有效解决人工生物酶“催化剂中毒”难题；创造性引入机器学习算法，提出靶向体系全局优化设计方法。综上，在解决金团簇-多肽靶向治疗机制等基础科学问题的同时，提出结构解析、靶向结合全局优化的高效新方法。