期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 27, 期 14, 页码 4731-4737出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202004705
关键词
carbohydrates; computational chemistry; conformational analysis; in vivo immunological evaluation; synthetic saponin adjuvants; vaccines
资金
- ERC [ERC-2016-STG-716878]
- Spanish Ministry of Science and Innovation [CTQ2017-87530-R, RYC-2015-17888, RTI2018-096494-B-100, RTI2018-099592-B-C22, SEV-2016-0644]
- Mizutani Foundation for Glycoscience [200077]
This study presents a 15-step synthesis of new linear trisaccharide variants of simplified QS-21-derived adjuvants, which replaced the complex carbohydrate chain with simpler disaccharides. In vivo immunological evaluation of the synthetic saponins showed attenuated antibody responses, indicating a negative impact of carbohydrate modifications on adjuvant activity.
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 beta-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.
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