基于动态组合策略的杂合糖簇的合成、筛选及其与蛋白质的超分子研究

Carbohydrate plays a significant role in many life activities. The biomimetic design and exploration of synthetic polysaccharides that are able to regulate the interaction in the pathogenesis between biological polysaccharides and proteins has become a research hotspot in recent years.This project aims to apply the biomimetic principle of multivalent effect of glycoclusters and dynamic combinatorial chemistry as a synthetic strategy to explore how to efficiently synthesize heteroglycoclusters with strong affinity for proteins and understand their interaction mechanism at the molecular level. We will first design and prepare a number of dithiol-based building blocks coupling with glucose, mannose, galactose and lactose moieties. Subsequently, they will be used to construct dynamic combination libraries which will be analyzed by LC/MS. The results will be compared with that from dynamic combination libraries in which lectin proteins act as target molecules, thereby we can identify and sort out the heteroglycoclusters that bind with the target proteins with strongest affinities. Finally, the recognition and co-assembly of the heteroglycoclusters and target proteins will be studied by means of isothermal titration calorimetry, nuclear magnetic resonance, electron microscopies and crystal X-ray diffractometry. Our research is at the interface between glycocalyx chemistry and dynamic combinatorial chemistry. The results will provide scientific basis for the development of new drugs, the detection and treatment of diseases.

糖类在许多生命活动中扮演着重要角色，近年来，通过仿生设计并开发出具有生物活性的多糖分子，对一些致病的多糖和蛋白质之间的识别作用进行调节，是领域内的研究热点。本申请旨在以多元糖基效应为仿生设计原则，动态组合化学为合成策略，高效合成与蛋白质具有强亲和力的杂合糖簇配体，并在分子水平上阐明杂合糖簇与蛋白质的超分子作用机制。我们将首先设计并制备出基于葡萄糖、甘露糖、半乳糖、乳糖等糖基的多个基于二硫化物的构建模块，利用它们构筑动态组合库，通过液质联用技术对体系进行分析，并与凝集素蛋白质作为靶标分子作用的动态组合库进行对比分析，从而筛选出与靶标蛋白亲和力最强的杂合糖簇配体。最后，通过等温滴定量热、核磁共振、电子显微镜和晶体X射线衍射仪等手段，对该杂合糖簇配体与靶标蛋白之间的识别与共组装进行研究。本项目是糖簇化学与动态组合化学的交叉研究，其结果将为新药开发、疾病检测与治疗提供科学依据。

动态组合化学是组合化学与超分子化学相交叉的新兴学科。该研究一般利用动态共价化学反应，将不同的构建模块以组合化学的方式，构筑成动态组合库，整个体系中的各个产物分子处于动态平衡，它们的浓度分布基于热力学平衡控制，相对稳定的产物将具有更大的浓度。当有一个外界因素介导到这个平衡时，平衡就会发生移动，产物分子的浓度分布会发生变化。我们利用该设计原则，设计了一系列二硫动态组合大环，引入了表面活性剂这样的小分子模板，利用共组装作为驱动力，构建了一个高效稳定的药物输送体系，为治疗耐药性肿瘤提供了新思路。另外，我们将拆分下来的糖分子，通过微波法，快速简便的制备了具有长余辉的室温磷光材料，为开发新一代的防伪技术奠定了基础。最后，我们还将二硫动态大环和传统的超分子柱芳烃大环进行了对比，通过结构调控，对二氧化钛光催化剂进行掺杂，实现了可见光催化水分解制备氢气，拓展了超分子大环在新能源开发中的应用。