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J. Biol. Chem., Vol. 281, Issue 4, 2317-2332, January 27, 2006

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Toward a Better Understanding of the Basis of the Molecular Mimicry of Polysaccharide Antigens by Peptides

THE EXAMPLE OF SHIGELLA FLEXNERI 5A^*

Marie-Jeanne Clément, Antoine Fortuné, Armelle Phalipon¶, Véronique Marcel-Peyre¶, Catherine Simenel, Anne Imberty||, Muriel Delepierre1, and Laurence A. Mulard**

From the Unité de RMN des Biomolécules, URA CNRS 2185, Institut Pasteur, ^**Unité de Chimie Organique, URA CNRS 2128, Institut Pasteur, ^¶Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, DPM UMR5063 UJF/CNRS, 5 Avenue de Verdun 38240 Meylan, France, and the ^||CERMAV-CNRS (affiliated with Université Joseph Fourier), 38041 Grenoble BP53, Cedex 09, France

Protein conjugates of oligosaccharides or peptides that mimic complex bacterial polysaccharide antigens represent alternatives to the classical polysaccharide-based conjugate vaccines developed so far. Hence, a better understanding of the molecular basis ensuring appropriate mimicry is required in order to design efficient carbohydrate mimic-based vaccines. This study focuses on the following two unrelated sets of mimics of the Shigella flexneri 5a O-specific polysaccharide (O-SP): (i) a synthetic branched pentasaccharide known to mimic the average solution conformation of S. flexneri 5a O-SP, and (ii) three nonapeptides selected upon screening of phage-displayed peptide libraries with two protective murine monoclonal antibodies (mAbs) of the A isotype specific for S. flexneri 5a O-SP. By inducing anti-O-SP antibodies upon immunization in mice when appropriately presented to the immune system, the pentasaccharide and peptides p100c and p115, but not peptide p22, were qualified as mimotopes of the native antigen. NMR studies based on transferred NOE (trNOE) experiments revealed that both kinds of mimotopes had an average conformation when bound to the mAbs that was close to that of their free form. Most interestingly, saturation transfer difference (STD) experiments showed that the characteristic turn conformations adopted by the major conformers of p100c and p115, as well as of p22, are clearly involved in mAb binding. These latter experiments also showed that the branched glucose residue of the pentasaccharide was a key part of the determinant recognized by the protective mAbs. Finally, by using NMR-derived pentasaccharide and peptide conformations coupled to STD information, models of antigen-antibody interaction were obtained. Most interestingly, only one model was found compatible with experimental data when large O-SP fragments were docked into one of the mIgA-binding sites. This newly made available system provides a new contribution to the understanding of the molecular mimicry of complex polysaccharides by peptides and short oligosaccharides.

Received for publication, September 15, 2005 , and in revised form, October 25, 2005.

^* This work was supported by MENRT (Programme de Recherche Fondamentale en Microbiologie et Maladies Infectieuses et Parasitaires), Délégation Générale pour l'Armement Contract 99 34 029, and the CNRS Program Physique et Chimie du Vivant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1S-4S.

⁵ V. Marcel-Peyre and A. Phalipon, unpublished data.

¹ To whom correspondence should be addressed: Unité de RMN des Biomolécules, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France. Tel.: 33-1-45-68-88-71; Fax: 33-1-45-68-89-29; E-mail: murield{at}pasteur.fr.

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