[Show abstract][Hide abstract] ABSTRACT: Protection against reinfection with noncapsulated Gram-negative bacteria, such as Shigella, an enteroinvasive bacterium responsible for bacillary dysentery, is mainly achieved by Abs specific for the O-Ag, the polysaccharide part of the LPS, the major bacterial surface Ag. The use of chemically defined glycoconjugates encompassing oligosaccharides mimicking the protective determinants carried by the O-Ag, thus expected to induce an efficient anti-LPS Ab response, has been considered an alternative to detoxified LPS-protein conjugate vaccines. The aim of this study was to identify such functional oligosaccharide mimics of the S. flexneri serotype 2a O-Ag. Using protective murine mAbs specific for S. flexneri serotype 2a and synthetic oligosaccharides designed to analyze the contribution of each sugar residue of the branched pentasaccharide repeating unit of the O-Ag, we demonstrated that the O-Ag exhibited an immunodominant serotype-specific determinant. We also showed that elongating the oligosaccharide sequence improved Ab recognition. From these antigenicity data, selected synthetic oligosaccharides were assessed for their potential to mimic the O-Ag by analyzing their immunogenicity in mice when coupled to tetanus toxoid via single point attachment. Our results demonstrated that induction of an efficient serotype 2a-specific anti-O-Ag Ab response was dependent on the length of the oligosaccharide sequence. A pentadecasaccharide representing three biological repeating units was identified as a potential candidate for further development of a chemically defined glycoconjugate vaccine against S. flexneri 2a infection.
The Journal of Immunology 03/2006; 176(3):1686-94. DOI:10.4049/jimmunol.176.3.1686 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The synthesis of three neoglycopeptides incorporating carbohydrate haptens, differing in length, covalently linked to a non natural universal T helper peptide is disclosed. They were synthesized according to a blockwise strategy based on the condensation of appropriate di-, tri-, and tetrasaccharide trichloroacetimidate donors onto an azidoethyl 2-acetamido-2-deoxybeta-D-glucopyranoside acceptor. Use of thiol-maleimide coupling chemistry allowed site-selective efficient conjugation.
[Show abstract][Hide abstract] ABSTRACT: The D'A'B'(E')C'DAB(E)C decasaccharide representative of a dimer of a frame-shifted pentasaccharide repeating unit of the O-specific polysaccharide of Shigella flexneri 2a was synthesized as its methyl glycoside by condensing a pentasaccharide donor (D'A'B'(E')C') and a pentasaccharide acceptor (DAB(E)C-OMe). Several convergent routes to these two building blocks, involving either the AB linkage or the BC linkage as the disconnection site, were evaluated in comparison to the linear strategy. The latter was preferred. It is based on the use of the trichloroacetimidate chemistry. The target branched oligosaccharide was designed to probe the recognition at the molecular level of the natural polysaccharide by protective monoclonal antibodies.
The Journal of Organic Chemistry 03/2004; 69(4):1060-74. DOI:10.1021/jo035125b · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An efficient synthesis of the methyl glycoside of a branched octasaccharide representative of Shigella flexneri serotype 2a O-specific polysaccharide is described. The synthesis is based on the use of the trichloroacetimidate methodology, and involves the condensation of a pentasaccharide acceptor and a trisaccharide donor as the key step.