Synthesis of Oligosaccharides Related to the O-Antigen of Shigella Flexneri Serotype 6 for Glycoconjugate Vaccine Development

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Synthesis of Oligosaccharides Related to the O-Antigen of Shigella Flexneri Serotype 6 for Glycoconjugate Vaccine Development

Olimpia Pitirollo 1 , Johan Cornil 1 , Rebecca Ulc, Pierre Chassagne, Laurence Mulard 1

1 Pasteur Institute, Paris, France

Shigella flexneri is a Gram-negative bacterium, causing shigellosis (or bacillary dysentery), an invasive intestinal infection that remains a major health concern in children living in developing countries [1]. Shigella flexneri 6 (SF6) is one of the most common circulating serotypes, and one to be included in a Shigella vaccine [2]. As an alternative to Shigella subunit vaccines involving polysaccharides from biological origin [3] , our group has been investigating the use of synthetic oligosaccharides as surrogates of the O-antigen (O-Ag), the polysaccharide component of the Shigella lipopolysaccharide. Such a vaccine candidate targeting S. flexneri 2a [4] was recently evaluated in human [5]. The repeating unit of the SF6 O-Ag is the linear tetrasaccharide ABCD [6]. Following early work on the identification of this O-Ag O-acetylation pattern and synthesis of short segments thereof [7], here we report a robust and scalable chemical synthesis of fully 3A/4A-O-acetylated or not tetra- and octasaccharides, featuring one and two SF6 O-Ag repeating units, respectively. These oligosaccharides were synthesized in a form compatible with their conjugation to a carrier and use for in vivo studies.

A robust [4+4] synthesis involving the imidate glycosylation chemistry was developed. In particular, tetrasaccharide building blocks enabling site-selective O-acetylation at rhamnose A and providing good stereocontrol at all glycosidic linkages were identified. Strategic choices and improvements compatible with scale up will be discussed.

→2)-[Ac→3/4]-45%-α-L-Rhap-(1→2)-α-L-Rhap-(1→4)-β-D-GalpA-(1→3)-β-D-GalpNAc-(1→ repeating unit (ABCD) of the SF6 O-Ag.

Kotloff K., Stine O. C. et al, Am. J. Trop. Med. Hyg., 2015, 93(5), 918-924

Baker S. and The H. C., Curr. Opin. Infect. Dis., 2018, 31(5), 449-454

L. A. Barel & L. A. Mulard, Human Vaccines and Immunotherapeutics (2019) doi: 10.1080/21645515.2019.1606972

van der Put R. et al, Bioconjugate Chem., 2016, 27(4), 883-892

https://clinicaltrials.gov/ct2/show/NCT02797236

Knirel Y.A. et al, Biochemistry, 2015, 80(7), 901-914

Chassagne P. et al, Eur. J. Org. Chem., 2013, 19, 4085-4106

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