Synthesis of Dendrimer-Type AIDS Vaccine Having High Antibody Productivity

从分子水平上设计并合成了一种具有较高抗HIV活性的树状分子艾滋病疫苗。携带高抗原性HIV多肽序列的中等分子量树枝状大分子疫苗有望产生大量抗体。核心树枝状大分子为赖氨酸第三代(G3)和第四代(G4)，以及鸟氨酸树枝状大分子第三代。建立了两种方法，在温和的条件下将HIV gp120中包含的多肽序列结合到树枝状大分子上。在第一种方法中，赖氨酸树状大分子G3中的8个氨基与乳糖、麦芽糖和麦芽三糖在BH3吡啶催化下进行还原胺化反应，得到最多16个低聚糖结合的树枝状大分子。在接下来的树枝状分子延伸中，低聚糖中的初级6-羟基与己二酸、琥珀酸等二元酸反应，得到二元酸-低聚糖-赖氨酸树枝状大分子。还制备了四层树枝状大分子。第二种方法合成了纤维二糖-赖氨酸树枝状大分子，其中纤维二糖部分的还原末端指向树枝状大分子的外部。为了还原的目的，尝试通过还原胺化结合HIV环肽来形成艾滋病疫苗。用核磁共振和飞行时间质谱仪测定了产物的结构和相对分子质量。得到了艾滋病疫苗的模型化合物。为了分析疫苗等生物活性大分子的作用机理，用核磁共振技术检测了多肽与多糖之间的分子间相互作用。

A dendrimer-type AIDS (acquired immunodeficiency syndrome) vaccine having a possibility of high anti-HIV (human immunodeficiency virus) activity was molecularly designed and synthesized. It is expected that a medium molecular weight dendrimer-type vaccine carrying highly antigenic HIV peptide sequence can produce a large quantity of antibodies. Lysine dendrimer third (G3) and fourth (G4) generations, and ornithine dendrimer third generation were used for core dendrimers. Two methods by which a peptide sequnece included in HIV gp120 was bound to the dendrimer under mild conditions were developed. In the first method, eight amino groups in lysine dendrimer G3 were reacted with lactose, maltose, and maltotriose by reductive amination using BH3 pyridine catalyst to produce at most 16 oligosaccharides-bound dendrimers. In the next dendrimer elongation, primary 6-OH groups in the oligosaccharide were reacted with such dibasic acids as adipic acid and suberic acid to give dibasic acid-oligosaccharide-lysine dendrimer three-layered dendrimers. A four-layered dendrimer was also preprared. In the second method, cellobiose-lysine dendrimer was synthesized in which reducing end of the cellobiose moiety was directed outward the dendrimer. To the reducing end, a HIV cyclic peptide was tried to bind by reductive amination to form AIDS vaccine. Structure and molecular weight of the products were determined by NMR and TOF-MS. A model compound for AIDS vaccine was obtained. Intermolecular interactions between polypeptide and polysaccharide were detected by NMR in order to analyze an action mechanism of biologically active macromolecules such as vaccine.