Chemical Immunology Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Biscay Science and Technology Park, Building 801A, 48160, Derio, Spain.
Computational Chemistry Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Biscay Science and Technology Park, Building 801A, 48160, Derio, Spain.
Chemistry. 2021 Mar 8;27(14):4731-4737. doi: 10.1002/chem.202004705. Epub 2021 Feb 4.
Adjuvants are key immunostimulatory components in vaccine formulations, which improve the immune response to the co-administered antigen. The saponin natural product QS-21 is one of the most promising immunoadjuvants in the development of vaccines against cancer and infectious diseases but suffers from limitations that have hampered its widespread human use. Previous structure-activity relationship studies have identified simplified saponin variants with truncated carbohydrate chains, but have not focused on the influence of the linear oligosaccharide domain of QS-21 in adjuvant activity. Herein, an expeditious 15-step synthesis of new linear trisaccharide variants of simplified QS-21-derived adjuvants is reported, in which the complex terminal xylose-rhamnose moiety has been replaced with commercially available, simpler lactose and cellobiose disaccharides in a β-anomeric configuration. In vivo immunological evaluation of the synthetic saponins showed attenuated antibody responses, highlighting the negative impact of such carbohydrate modifications on adjuvant activity, which could be associated with higher saponin conformational flexibility.
佐剂是疫苗配方中的关键免疫刺激性成分，可增强对共同给予的抗原的免疫反应。皂素天然产物 QS-21 是癌症和传染病疫苗开发中最有前途的免疫佐剂之一，但存在一些限制，阻碍了其在人类中的广泛应用。以前的结构-活性关系研究已经确定了具有截短碳水化合物链的简化皂素变体，但没有关注 QS-21 线性寡糖结构域对佐剂活性的影响。本文报道了一种快速的 15 步合成方法，可得到新型简化 QS-21 衍生佐剂的线性三糖变体，其中复杂的末端木糖-鼠李糖部分已被商业上可获得的更简单的β-构型乳糖和纤维二糖双糖所取代。对合成皂素的体内免疫学评价表明，抗体反应减弱，这突出表明这种碳水化合物修饰对佐剂活性的负面影响，这可能与更高的皂素构象灵活性有关。
