Two different methods result in the selection of peptides that induce a protective antibody response to Neisseria meningitidis serogroup C

Prinz, Deborah M.; Smithson, S. Louise; Westerink, M. A. Julie

doi:10.1016/j.jim.2003.08.005

Cited by 35 publications

(24 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most interestingly, the mimotopes share no obvious consensus sequence and do not cross-react with one another. However, as often reported by others (29,30), their amino acid sequences contain aromatic and hydrophobic residues but also amino acids having cyclic side chains, including at least one proline.…”

mentioning

confidence: 54%

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

Clément

Fortuné

Phalipon

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

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 phagedisplayed 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 NMRderived 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.

show abstract

mentioning

confidence: 54%

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

Clément

Fortuné

Phalipon

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…For a peptide to succeed as an immunogen that can generate a specific anticarbohydrate antibody response, carbohydratepeptide cross-reactivity must translate into immunogenic mimicry (i.e., the ability of a crossreactive peptide to elicit that same antibody, or functionally similar ones). Immunogenic mimicry of carbohydrate epitopes by peptides has been previously reported (22)(23)(24)(25)(26)(49)(50)(51), which suggests that cross-reacting peptides may elicit antibodies functionally equivalent to those elicited by carbohydrate epitopes. In contrast, our preliminary immunization of rabbits with recombinant 2G12.1 phage produced a significant antipeptide response but no crossreactivity with gp120, indicating that 2G12.1 elicits an antibody response that is qualitatively different from 2G12 (see Supplemental Table 3 and Supplemental Fig.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 93%

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

Menéndez

Calarese

Stanfield³

et al. 2008

FASEB j.

View full text Add to dashboard Cite

MAb 2G12 neutralizes HIV-1 by binding with high affinity to a cluster of high-mannose oligosaccharides on the envelope glycoprotein, gp120. Screening of phage-displayed peptide libraries with 2G12 identified peptides that bind specifically, with K d s ranging from 0.4 to 200 μM. The crystal structure of a 21-mer peptide ligand in complex with 2G12 Fab was determined at 2.8 Å resolution. Comparison of this structure with previous structures of 2G12-carbohydrate complexes revealed striking differences in the mechanism of 2G12 binding to peptide vs. carbohydrate. The peptide occupies a site different from, but adjacent to, the primary carbohydrate-binding site on 2G12, and makes only slightly fewer contacts to the Fab than Man 9 GlcNAc 2 (51 vs. 56, respectively). However, only two antibody contacts with the peptide are hydrogen bonds in contrast to six with Man 9 GlcNAc 2 , and only three of the antibody residues that interact with Man 9 GlcNAc 2 also contact the peptide. Thus, this mechanism of peptide binding to 2G12 does not support structural mimicry of the native carbohydrate epitope on gp120, since it neither replicates the oligosaccharide footprint on the antibody nor most of the contact residues. Moreover, 2G12.1 peptide is not an immunogenic mimic of the 2G12 epitope, since antisera produced against it did not bind gp120.-Menendez, A., Calarese, D. A., Stanfield, R. L., Chow, K. C., Scanlan, C. N., Kunert, R., Katinger, H., Burton, D. R., Wilson, I. A., Scott, J. K. A peptide inhibitor of HIV-1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHuman monoclonal antibody (MAb) 2G12 efficiently neutralizes a broad range of HIV-1 primary isolates in vitro (1-3) and protects from in vivo viral challenge in macaques in combination with other antibodies (4-6). MAb 2G12 binds with high affinity to a unique, conserved epitope on the HIV-1 envelope that is formed by a cluster of N-linked, high-mannose glycan groups on the "silent" face of gp120 (7-10). Crystal structures of 2G12 Fab alone, and in complex with oligosaccharides Man 9 GlcNAc 2 and Manα1-2Man, revealed that two Fab monomers assemble into an interlocked, domain-swapped dimer, that forms an extensive, multivalent binding surface (11). Four Man 9 GlcNAc 2 moieties were observed bound to the Fab dimer in the crystal structure, occupying the two canonical antigen-binding sites, and two novel ones located at the assembled interface of the two interlocked V H domains. Since the identification of its epitope, MAb 2G12 has received significant attention as a template for HIV-1 vaccine development. Considerable effort has been directed at characterizing its oligosaccharide-binding profile (12)(13)(14)(15), and the generation of novel antigens in the form of synthetic oligomannoses (13,16,17) or short, synthetic glycopeptides (18-20). In an attempt to generate immunogens that elicit 2G12-like antibodies, we chose to isolate peptides t...

show abstract

“…An analysis of the amino acid composition of phageborne peptides identified in screenings with antibodies shows that, occasionally, the incidence of proline is higher than that supported solely by the frequency of proline codons [68][69][70][71][72][73]. Some of this high incidence may be explained by the fact that proline is overrepresented in many primary PDPLs ( [74], and references therein) .…”

Section: Phage-borne Peptides With High-proline Contentmentioning

confidence: 99%

The nature of target-unrelated peptides recovered in the screening of phage-displayed random peptide libraries with antibodies

Menéndez

Scott

2005

Analytical Biochemistry

113

105

View full text Add to dashboard Cite

Two different methods result in the selection of peptides that induce a protective antibody response to Neisseria meningitidis serogroup C

Cited by 35 publications

References 67 publications

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

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

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

The nature of target-unrelated peptides recovered in the screening of phage-displayed random peptide libraries with antibodies

Contact Info

Product

Resources

About