4-胺基阿拉伯糖基修饰的活性寡糖分子lipid A及衍生物的合成研究

Lipid A作为格兰仕阴性细菌表面脂多糖的重要组成部分是致病菌的免疫原性和毒性的主要原因。尽管不同结构的Lipid A分子的生物活性被广泛的研究，且催生了在免疫药物研究历史上具有里程碑意义的免疫佐剂SM-MPLA，但受到获取困难的限制，更加复杂的1,4’位膦酸上以4-胺基阿拉伯糖修饰的Lipid A(1)分子的生物活性研究进展缓慢。通过基因工程技术的研究初步表明Lipid A的4-胺基阿拉伯糖修饰对细菌的多种生理功能具有重要的作用。本课题拟开展对1,4’位以4-胺基阿拉伯糖基膦酸酯修饰的Lipid A及其衍生物的合成研究，以期建立一条多样化合成路线，从而获取均一、高纯度的Lipid A寡糖化合物，从根本上解决该类化合物的获取难题，推动精准的化学结构与生物活性关系的研究，促进药物先导化合物的发现。此外，本课题将发展异头位糖基膦酸酯合成新策略，推动糖基膦酸酯类寡糖疫苗的合成进展。

Lipid A as the component of lipopolysaccharides from Gram (-) bacteria surface is proved to be the major cause of the immunogenicity and toxicity of these pathogens. The relationships of a variety of structurally modified Lipid As and biological activities have been investigated, which brought up the most important adjuvant SM-MPLA in the research field of immunological medicines, nevertheless, the complex 4-amino-4-dexoxy-arabinose modified Lipid A (1) is rarely studied, presumably due to the lack of efficient approach to these compounds. Moreover, the 4-amino-4-dexoxy-arabinosyl moieties at 1 and 4’positions of Lipid A are revealed to be closely related to physiological functions of bacteria via the genetic engineering technology. Herein, we plan to develop a general and diverse synthetic route to Lipid A (1) and its derivatives, thereby providing sufficient quantity of homogeneous and pure Lipid As to drive the accurate structure-bioactivity relationship studies and the discovery of lead compounds. Moreover, the novel strategy for synthesizing glycosyl phosphates will be developed, which would streamline the synthesis of phosphoryl oligosaccharide vaccines.