合成高度甘露糖寡醣發展愛滋病疫苗

Abstract

本論文中，探討人類免疫缺乏病毒表面抗原的合成，利用化學合成策略，快速得到病毒表面有用的多醣體抗原，期盼這樣的人工合成抗原能夠在疫苗的發展能夠有更進一步的了解與開發。 基於翁啟惠老師在美研究團隊的研究成果，人工所合成的抗原分子Man4相較於病毒表面上完整的抗原分子Man9GlcNAc2有更佳的效果，發現在利用酵素免疫分析法辨認2G12抗體有更佳的結合力，因此本篇論文旨在利用polylysines與Man4進行1,3-偶極環化加成反應，利用疊氮化物(Azides)與炔類化合物(alkynes)所形成的三唑類，使得在30Å的奈米級的大小之下能夠提高辨識抗原的密度。並且將此多價分子抗原與免疫源分子進行偶合反應，以提高我們的抗原分子在人體上之免疫反應。 本論文嚐試了一些不同類型的糖基化反應，並且期望能設計一個產率較佳的一鍋化合成策略，由於在一鍋化合成之後產物的分離較困難，所以我必須先得到Man4，其乃是利用兩個甘露糖構築體進行三次醣基化反應及兩次的水解反應而獲得。另外一個八價分子polylysine則是以Ｌ-離胺酸作為起始物，經過一連串的化學反應即可合成。之後將此八價分子與Man4產物進行1,3-偶極環化加成反應。而此偶合反應將會在液相合成，預期會有更好的耦合效果，並致力於日後在疫苗製作的合成。

In this thesis, a more efficient and abundant synthetic pathway to synthesize the high mannose type oligosaccharide antigen was studied. This antigen was design to induce the immune response for HIV-1. So I have used the D-mannose as starting material to afford different glycosyl donors and tried to synthesize the high mannose oligosaccharide antigen in one-pot condition. However, the final product was obtain with low purity and other impurities difficult to remove by purification procedure. Finally, I just approach to synthesize of highmannose type oligosaccharide from both of glycosyl donors 23 and acceptors 25 using step by step strategies in highly yield and purity. The oligomannose 56 have a linker part with azido functional group for the 1,3-dipolarcycloaddtion. On the other hand, the dendrimer was design to increase the density of the high mannose type oligosaccharide on the carrier protein. I use the L-lysine as the starting matrial to construct the dendrimer. The termial amino functional group would be change to alkynyl functional group using propiolic acid, which would be induce for 1,3-dipolarcycloaddtion for the connect the oligomannose and the dendrimer.