Synthetic Studies on the Zwitterionic Disaccharide Repeating Unit from the Shigella Sonnei Polysaccharides and Its Oligomerization

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Synthetic Studies on the Zwitterionic Disaccharide Repeating Unit from the Shigella Sonnei Polysaccharides and Its Oligomerization

Debashis Dhara 1 , Hélène B. Pfister 1,2 , Julie Paoletti 1 , Marion Bouchet 1 , Laurence A. Mulard 1

1 Chimie des Biomolécules, Institut Pasteur, UMR3523, CNRS, 28 rue du Dr Roux, 75724 Paris Cedex 15, France, 2 Université Sorbonne Paris Cité, Paris, , France

Shigellosis is a diarrheal disease caused by a family of bacteria named Shigella. Phase III trials have demonstrated the protective capacity of a Shigella sonnei detoxified lipopolysaccharide-conjugate against S. sonnei infection in young adults and children older than 3 years of age.[1] As a possible alternative towards a highly immunogenic S. sonnei vaccine, we have engaged in the use conjugates made of synthetic oligosaccharides covalently attached to a carrier protein.

The S. sonnei polysaccharides feature a zwitterionic disaccharide repeat encompassing two rare monosaccharides, a 2-acetamido-2-deoxy-L-altruronic acid (residue A) and a 2-acetamido-4-amino-2,4,6-trideoxy-D-galactopyranose (AAT, residue B), 1,2-trans linked to one another. This communication will report our investigations on the synthesis of oligosaccharides that have the {-D-FucpNAc4N-(1→}0,1[4)--L-AltpNAcA-(1→3)--D-FucpNAc4N-(1→]1,2,3…{4)--L-AltpNAcA}0,1 core sequence (B0,1(AB)1,2,3…A0,1) (Figure 1).[2]

Focus is on the identification of a suitable orthogonally protected AB disaccharide compatible with chain elongation at both ends, release in its free form, and subsequent site-selective conjugation onto a carrier or solid support. The synthesis of such a disaccharide intermediate, obtained by the post-glycosylation oxidation strategy, will be presented with emphasis on the selected A and B precursors, and their preparation from L-glucose and D-glucosamine, respectively. Besides, proper protecting group manipulation ensuing that a robust [A+B] glycosylation is achieved and the feasibility of the overall strategy will be exemplified for the (AB)3 hexasaccharide.

Figure 1: Schematic representation of the synthetic challenges.

Passwell, J. H.; Ashkenazi, S.; Miron, D.; Ramon, R.; Farzam, N.; Lerner-Geva, I.; Levi, Y.; MHA and the israel Shigella study group.; Chu, C., Shiloach, J.; Robbins, J. B.; Schneerson R.; Safety and immunogenicity of Shigella sonnei-CRM9 and Shigella flexneri type 2a-rEPAsucc conjugate vaccines in one- to four-year-old children. Pediatr. Infect. Dis. J. 2003, 22, 701-706.

Pfister, H. B.; and Mulard, L. A.; Synthesis of the zwitterionic repeating unit of the o-antigen from Shigella sonnei and chain elongation at both ends. Org. Lett. 2014, 16, 4892-4895.

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