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

University of Grenoble, Grenoble, Rhône-Alpes, France
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2006; 281(4):2317-2332. DOI: 10.1074/jbc.M510172200
Source: PubMed


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.

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Available from: Muriel Delepierre,
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    • "Often times CMPs share no obvious consensus sequence but their amino acid sequences often contain aromatic and hydrophobic residues but also amino acids having cyclic side chains, including proline and glycine that affects the conformational properties of the mimic (13, 57). The predominance of aromatic residues in CMPs invokes interaction scenarios that include stacking and hydrophobic interactions. "
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    ABSTRACT: Molecular mimicry is fundamental to biology and transcends to many disciplines ranging from immune pathology to drug design. Structural characterization of molecular partners has provided insight into the origins and relative importance of complementarity in mimicry. Chemical complementarity is easy to understand; amino acid sequence similarity between peptides, for example, can lead to cross-reactivity triggering similar reactivity from their cognate receptors. However, conformational complementarity is difficult to decipher. Molecular mimicry of carbohydrates by peptides is often considered one of those. Extensive studies of innate and adaptive immune responses suggests the existence of carbohydrate mimicry, but the structural basis for this mimicry yields confounding details; peptides mimicking carbohydrates in some cases fail to exhibit both chemical and conformational mimicry. Deconvolution of these two types of complementarity in mimicry and its relationship to biological function can nevertheless lead to new therapeutics. Here, we discuss our experience examining the immunological aspects and implications of carbohydrate-peptide mimicry. Emphasis is placed on the rationale, the lessons learned from the methodologies to identify mimics, a perspective on the limitations of structural analysis, the biological consequences of mimicking tumor-associated carbohydrate antigens, and the notion of reverse engineering to develop carbohydrate-mimetic peptides in vaccine design strategies to induce responses to glycan antigens expressed on cancer cells.
    Frontiers in Immunology 06/2014; 5:308. DOI:10.3389/fimmu.2014.00308
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    • "This supports, in serotype-specific immune sera, the dominant recognition of epitopes containing more than three backbone residues, which is the maximal size of oligosaccharide segments shared between two or more S. flexneri O-Ags. Besides, this assertion matches the available data for murine protective mAbs specific for the O-Ags of S. flexneri Y (Vyas et al. 2002), S. flexneri 5a (Clement et al. 2006) and 2a (Phalipon et al. 2006; Vulliez-Le Normand et al. 2008). "
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    ABSTRACT: The O-antigen (O-Ag), the polysaccharide part of the lipopolysaccharide, is the major target of the serotype-specific protective humoral response elicited upon host infection by Shigella flexneri, the main causal agent of the endemic form of bacillary dysentery. The O-Ag repeat units (RUs) of 12 S. flexneri serotypes share the tetrasaccharide backbone →2)-α-l-Rhap-(1 → 2)-α-l-Rhap-(1 → 3)-α-l-Rhap-(1 → 3)-β-d-GlcpNAc-(1→, with site-selective glucosylation(s) and/or O-acetylation defining the serotypes. To investigate the conformational basis of serotype specificity, we sampled conformational behaviors during 60 ns of molecular dynamic simulations for oligosaccharides representing three RUs of each one of the O-Ags corresponding to serotypes 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, X and Y, respectively. The calculated trajectories were checked by nuclear magnetic resonance (NMR) for 1a, 2a, 3a and 5a O-Ags. The simulations predict that in all O-Ags, but 1a and 1b, serotype-specific substitutions of the backbone do not induce any new backbone conformations compared with the linear type O-Ag Y, although they restrain locally the accessible conformational space. Moreover, the influence of any given substituent on the backbone is independent of the eventual presence of other substituents. Finally, only slight differences in conformational behavior between terminal and inner RUs were observed. These results suggest that the reported serotype-specificity of the protective immune response is not due to recognition of distinct backbone conformations, but to binding of the serotype-defining substituents in the O-Ag context. The gained knowledge is discussed in terms of impact on the development of a broad-serotype coverage vaccine.
    Glycobiology 10/2010; 21(1):109-21. DOI:10.1093/glycob/cwq136 · 3.15 Impact Factor

  • 19th American Peptide Symposium; 01/2006
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