新型白念株菌疫苗的设计、合成及免疫活性评价

Fungal infections especially caused by Candida albicans were a continuous and serious threat to human health and life especially to immunocompromised patients, moreover, triazole agents has suffered severe drug resistance. Therefore, new anti-fungal treatment strategies are urgently needed in clinical. At present, the sugar and protein structure and function of the cell surface of Candida albicans has been partially clarified, in which glycosyl phosphatidylinositol anchored proteins was closely related to fungal invasion, adhesion, phagocytosis, these proteins has been used in the preparation of fungal vaccines. In this project, we will select protein fragments which were expressed by Als1, Als3, Hwp1 Pga59, Sap9 five kinds of gene, the protein fragments will be connected with beta-1,2-oligomeric mannose sugar by common glycoproteins phosphate ethanolamine-based groups. The glycoproteins phosphate ethanolamine-based groups can enhance the β-1,2 - oligomers of mannose immunogenicity. 5 new glycopeptide molecules as vaccine will be synthesised as well as their in vitro and in vivo activity against Candida albicans will be investigated. This project will provide new strategies and approaches for the prevention and treatment of anti-fungal infection.

由白念珠菌导致的各种感染疾病在临床上不仅发病率很高，而且感染所导致的死亡率也居高不下。另外，白念珠菌对各类抗真菌药物的耐药性问题也非常严重。因此，临床上急需全新的抗真菌治疗策略。目前，白念珠菌细胞表面的糖及蛋白的结构和功能已被部分阐明，其中糖基化的磷脂酰肌醇锚定的各种蛋白与真菌的侵入、粘附、吞噬等密切相关，这些蛋白具有一定的免疫原性并已被用于制备真菌疫苗。本项目我们将选择具有这些功能的蛋白片断，包括Als1， Als3，Hwp1，Pga59，Sap9五种基因表达的蛋白片段，通过常见的糖蛋白连接基团磷酸乙醇胺基与已经证明具有一定免疫原性的β-1,2-寡聚甘露糖进行连接，以增强β-1,2-寡聚甘露糖的免疫原性，共合成系列全新结构的糖肽分子，并将其作为针对白念珠菌的真菌疫苗，对其进行体内外的预防白念株菌感染的能力测定，探讨其作用机理，为抗真菌感染的预防和治疗提供新的策略和途径。

由白念珠菌导致的各种感染疾病在临床上不仅发病率很高，而且感染所导致的死亡率也居高不下。另外，白念珠菌对各类抗真菌药物的耐药性问题也非常严重。因此，临床上急需全新的抗真菌治疗策略。目前，白念珠菌细胞表面的糖及蛋白的结构和功能已被部分阐明，其中糖基化的磷脂酰肌醇锚定的各种蛋白与真菌的侵入、粘附、吞噬等密切相关，这些蛋白具有一定的免疫原性并已被用于制备真菌疫苗。本项目我们将选择具有这些功能的蛋白片断，包括Als1， Als3，Hwp1，Pga59，Sap9五种基因表达的蛋白片段，通过常见的糖蛋白连接基团磷酸乙醇胺基与已经证明具有一定免疫原性的β-1,2-寡聚甘露糖进行连接，以增强β-1,2-寡聚甘露糖的免疫原性，共合成6个全新结构的糖肽分子，并将其作为针对白念珠菌的真菌疫苗，体外免疫原型测试表明，目标化合物显示出一定的免疫原型，进一步药理活性研究正在进行中，本课题的顺利开展为抗真菌感染的预防和治疗提供新的策略和途径。