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Chemical synthesis elucidates the key antigenic epitope of the autism-related bacterium Clostridium bolteae capsular octadecasaccharide

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Shen,  Dacheng
Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Seeberger,  Peter H.
Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Citation

Yin, J., Cai, J., Hu, J., Qin, C., Li, L., Shen, D., et al. (2020). Chemical synthesis elucidates the key antigenic epitope of the autism-related bacterium Clostridium bolteae capsular octadecasaccharide. Angewandte Chemie International Edition, 59(46), 20529-20537. doi:10.1002/anie.202007209.


Cite as: http://hdl.handle.net/21.11116/0000-0006-CEAB-2
Abstract
The gut pathogen Clostridium bolteae has been associated with the onset of autism spectrum disorder (ASD). To create vaccines against C. bolteae, it is important to identify exact protective epitopes of the immunologically active capsular polysaccharide (CPS). Here, we prepared a series of C. bolteae CPS glycans up to an octadecasaccharide. Key to achieving the total syntheses is a [2+2] coupling strategy based on a ß-d-Rha p -(1→3)-α-d-Man p repeating unit that in turn was accessed via a stereoselective ß-d-rhamnosylation. The 4,6- O -benzylidene-induced conformational locking is a powerful strategy for forming ß-d-mannose-type glycoside. An indirect strategy based on the C2 epimerization of ß-d-quinovoside was efficiently achieved by Swern oxidation and borohydride reduction. Sequential glycosylation, regioselective and global deprotection produced disaccharide, tetrasaccharide, all the way to octadecasaccharide. Glycan microarrays analysis of sera from rabbits immunized with inactivated C. bolteae bacteria revealed a humoral immune response to di- and tetrasaccharide but none of the longer sequences. Tetrasaccharide may be a key motif for designing glycoconjugate vaccines against C. bolteae .