具核梭杆菌ATCC 23726脂多糖O-抗原三糖的全合成及其免疫活性研究

具核梭杆菌是一种人类口腔和肠道致病菌，其对结直肠癌细胞增殖、肿瘤免疫逃逸和化疗耐药性等有促进作用。鉴于具核梭杆菌的抗生素耐药性不断提高，疫苗的开发迫在眉睫。具核梭杆菌ATCC 23726菌株的脂多糖O-抗原具有高度的结构特异性，是疫苗开发中很有潜力的免疫靶点。本课题拟以具核梭杆菌ATCC 23726的O-抗原三糖重复单元为目标分子，基于氨基正交保护、稀有基团选择性组装和巯基连接臂应用等策略的发展实现其化学全合成，并从糖链长度和修饰基团等方面出发制备包含寡糖片段和衍生物的抗原库。通过基于糖芯片技术的血清筛查、小鼠免疫实验，结合细胞流式技术和STD-NMR技术，明确具核梭杆菌ATCC 23726型O-抗原三糖的免疫表位及其构效关系，进而为糖缀合疫苗开发奠定理论基础。此外，该O-抗原三糖的化学全合成，将为其它高密度氨基糖的高效制备提供参考。

Fusobacterium nucleatum, a human intestinal and oral pathogenic bacterium, promotes colorectal cancer proliferation, tumor immune evasion and resistance to chemotherapy. A F. nucleatum vaccine would be highly desirable for prevention and treatment of F. nucleatum infection as antibiotic resistance increases. Since no F. nucleatum vaccine is available, the structurally unique lipopolysaccharide O-antigen from F. nucleatum strain ATCC 23726 is thought to be a potential target for developing vaccine. This study focuses on chemical synthesis and immunological study of the F. nucleatum strain ATCC 23726 O-antigen trisaccharide repeating unit. The orthogonal protection strategy for amino groups, the selective installation of rare functional groups and the application of thiol linker will be involved in the total synthesis of F. nucleatum ATCC 23726 O-antigen trisaccharide. To explore the detailed structure and immunological activity relationship, a F. nucleatum ATCC 23726 O-antigen oligosaccharides library will be constructed with varied saccharide chain length, with or without the functional groups. The oligosaccharide antigens will be used in immunization and microarray analysis to investigate their immunological properties. After preparation of monoclonal antibodies, STD-NMR will be applied to analyze antigen-antibody interactions. Significantly, the elucidation of the structure and immunological activity relationship of F. nucleatum ATCC 23726 O-antigen trisaccharide in this study will form a theory base for future F. nucleatum vaccine development. In addition, the synthesis of F. nucleatum ATCC 23726 O-antigen trisaccharide will provide valuable reference for the syntheses of other densely functionalized aminoglycosides.