环二肽自组装: 分子设计，结构调控和免疫活性的研究

Self-assembly based on peptides have broad prospects in the biological application and tissue engineering due to their unique advantages, such as simplicity structure, ease of synthesis and chemical modification, biocompatibility and strong capability of assembly. It is of great importance to develop new nanomaterials of bioactive peptide via self-assembly and uncover relationships between their functionalities and inner mechanisms. In this research project, we select bioactive cyclic dipeptides as assembly units, through appropriate molecular design (particularly the type of amino acid) to coordinate the multiple non-covalent interactions of molecules. The influences of the supramolecular architectures and self-assembly dynamic process will be investigated by changing the assembly conditions, and the mechanism of the self-assembly will be revealed. Subsequently, we plan to take macrophages as the primary immune cells model, investigate the proliferation, phagocytosis capability of macrophages and their expression of proinflammatory cytokines by exposure to the cyclic dipeptide self-assembled nanostructures, and the connection between the self-assembled nanostructures and their immune activities will be discussed. Based on the above, we will fabricate peptide-based nanomaterials with high immune activities via controlled assembly, and the outcome of this research could provide experimental and theoretical basis for the self-assembly，all of which would facilitate the biomedicine application of bioactive peptide-based nanomaterials.

肽基自组装材料以其简单成熟的合成方法、易于化学修饰和功能化、易于组装和生物相容性好等优势，在生物医药和组织工程方面具有巨大的应用潜力。开发活性肽分子的组装纳米材料，深化其生物活性功能是该领域的研究热点和难点。本项目拟选取具有六元环刚性结构和显著生物活性的环二肽分子作为组装基元，通过优化设计环二肽的氨基酸残基的结构和组装条件，研究如何调控分子间的多种弱相互作用以实现对其自组装结构的调控，阐明组装体的形成过程及机理。进一步地，以巨噬细胞为模型，研究环二肽纳米组装体对其活化、增殖、吞噬和前炎症因子分泌情况的影响。探索环二肽组装体的结构、尺寸、表面性质等与其增强免疫活性之间的关系。本项目通过对环二肽组装体系的理解和认识，构建具有高免疫活性的纳米组装材料，为新型肽基纳米材料的自组装及其生物学应用提供实验和理论上的科学依据。

环二肽(CDPs)作为许多活性天然产物的骨架，由于其独特的生物和药理活性，如抗肿瘤、抗菌、免疫调节等引起了人们的广泛关注。本项目主要通过调控分子间的弱相互作用，实现了环二肽的可控纳米结构制备，有效解决了环二肽水溶性差、易结晶、生物利用度低的问题，为其体内生物利用奠定了基础。具体包括：（1）发展了一种基于环二肽(cyclo-(Leu-Phe)，CLF)的多功能水凝胶，它可在各种极端条件下，例如酸性、碱性、含有盐、蛋白或酶的溶液，形成具有良好的稳定性、可调节的流变特性的水凝胶，拓展了肽基软材料的生物利用范围。（2）基于ICG介导的CDPs疏水自组装，通过调控分子间氢键、π-π堆积等弱相互作用，获得了在水溶液中分散性良好的环二肽纳米带。该环二肽纳米带的形貌、大小可控，可以通过调控动力学参数得到不同长度的纳米纤维及纳米带。同时，纳米带的结构促进了细胞对环二肽的摄取，有利于实现环二肽的抗肿瘤活性。这为开发用于生物医学和工程应用的先进软材料提供了新的思路。