基于糖肽分子自组装构建新型细胞支架材料和抑菌材料的研究

Extracellular matrix (ECM) play an important role in biological system by working as biocompatible scaffolds with appropriate biomechanical and chemical properties to allow the adhesion, growth, and survival of cells. With the purpose of solving the problem of low cell-adhesion ability of peptide-based ECM, we propose to use glycopeptide to work as a building block to prepare novel biomimetic ECM through supramolecular self-assembly, because of the high similarity of glycopeptide hydrogels to ECM in both structural morphology and composition. Glycopeptide as a class of biomolecules between glycoprotein and glycoamino acid, is a peptide derivative that contains carbohydrate moieties covalently attached to the side chains of the amino acid residues. Because of many primitive advantages, such as biostability, biocompatibility, self-assembling and cell adhesion, glycopeptide has attracted great attention and become a novel platform for building-up novel biofunctional materials. Aiming at the above issues, the author proposes to prepare a series of glycopeptides from different saccharides and tyrosine phosphate (a substrate of alkaline phosphatase), and explore their potentials to form supramolecular hydrogel via enzymatic reaction under physiological conditions, because mild gelation condition is a prerequisite for the preparation of biomimetic ECM for biological applications. The saccharide groups on the molecule of glycopeptide can form sugar-clusters on the surface of self-assembled materials to promote cell adhesion between cells and gel matrix via multivalent sugar-lectin and sugar-sugar interactions. From this proposed study, we expect that it can not only generate novel candidates of biomaterials from glycopeptide to mimic the functions of ECM, but also provide innovative substances and new method to prepare novel antibacterial materials.

在组织工程学研究中，细胞外基质替代物即基质材料的研究是一个至关重要的方面，是目前限制其发展和应用的一个瓶颈。本项目针对目前多肽自组装细胞支架材料细胞黏附性差的不足，拟利用具有细胞特异性识别能力和自组装特性的糖肽分子为基础单元，通过超分子自组装方法，构建具有良好细胞黏附性的新型细胞支架材料。通过酶响应性底物分子的引入，可实现在温和的生理条件下制备具有良好细胞相容性的糖肽自组装材料，解决目前诱导糖肽超分子自组装的条件因素较苛刻的弊端；具有细胞特异性识别能力的糖苷基团的使用可以调节材料与细胞的特异性识别，提高糖肽自组装材料对多种细胞的黏附作用，起到促进动物细胞生长和抑制细菌繁殖的作用。以上研究工作的开展不仅为构建新型的细胞外基质替代物提供了新的构筑基元，也为进一步研制新型抑菌材料提供了创新的物质基础。

本项目通过利用具有自组装特性的多肽分子、碱性磷酸酶敏感的酪氨酸磷酸分子以及带有细胞亲和性以及细胞识别能力的多种寡糖分子（葡萄糖、半乳糖和甘露糖）为基础单元，制备了具有酶敏感糖肽自组装分子，实现在温和的生理条件下制备具有多种细胞（动物细胞和细菌）黏附作用的糖肽自组装体，并系统研究了多肽糖化修饰对调节多肽分子的自组装特性、纳米形貌、力学性能、热力学和生物稳定性的影响规律，以及在促进动物细胞附着和生长和抑制细菌繁殖方面的应用潜力，并得到了结论性的数据。首先，利用多肽固相合成反应制备含有酪氨酸磷酸分子和糖基官能团的糖肽自组装前体分子，并证明了该合成方法和制备路线的可行性；其次，系统研究碱性磷酸酶的脱磷酸反应对诱导糖肽自组装前体分子自组装水凝胶的效果；以及糖化修饰对多肽分子自组装能力和微观纳米结构、力学性能、热力学和生物稳定性的影响规律；最后，研究了该系列糖肽自组装体在制备具有良好抑制细菌存活，同时又能促进细胞生长的培养基体上的应用潜力。该项研究课题的开展可以改善多肽骨架的细胞亲和性，丰富自组装分子的结构，构建出具有多种细胞黏附特性的仿细胞外基质的细胞支架材料和抑菌材料。