A Molecular Basis for Functional Peptide Mimicry of a Carbohydrate Antigen

Luo, Ping; Canziani, Gabriela; Cunto-Amesty, Gina; Kieber‐Emmons, Thomas

doi:10.1074/jbc.m909121199

Cited by 55 publications

(55 citation statements)

References 44 publications

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“…Peptides 104 and 105 are carbohydrate mimics and induction of carbohydrate and cellreactive functional serum Abs by immunization with these peptides has been shown in our previous works (23,25,26). Peptide 107 binds to both GS-I and WGA lectins, and the data suggest that this peptide may mimic multiple oligosaccharides involved in tumor cell apoptosis.…”

Section: Therapeutic Dna Immunization Arrested Liver Metastasismentioning

confidence: 98%

“…The 107-peptide was identified and selected based on its reactivity with both GS-I and WGA with an expectation that, upon immunization, serum Abs cross-reactive with multiple carbohydrate structures would be induced. The peptides 104, 106, 107, and 109 all bind to an anti-Lewis Y Ab (23,25,26) and induce serum Abs cross-reactive with Lewis Y-expressing breast cancer cells, which mediated tumor cell killing by a CDC mechanism (5). We have shown before that mimotopes of core structures of tumorassociated carbohydrate Ags are particularly advantageous to augment the cross-reactive carbohydrate immune response because they can function as priming agents to expand B cells to multiple carbohydrate Ags upon boosting with nominal Ag (30).…”

Section: Discussionmentioning

confidence: 99%

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Reduction of Spontaneous Metastases through Induction of Carbohydrate Cross-Reactive Apoptotic Antibodies

Monzavi‐Karbassi

Artaud

Jousheghany

et al. 2005

The Journal of Immunology

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The selective targeting of tumor-associated carbohydrate Ags by the induction of serum Abs that trigger apoptosis of tumor cells as a means to reduce circulating tumor cells and micrometastases would be an advantage in cancer vaccine development. Some plant lectins like Griffonia simplicifolia lectin I and wheat germ agglutinin mediate the apoptosis of tumor cells. We investigated the possibility of using these lectins as templates to select peptide mimotopes of tumor-associated carbohydrate Ags as immunogens to generate cross-reactive Abs capable of mediating apoptosis of tumor cells. In this study, we show that immunization with a mimotope selected based on its reactivity with Griffonia simplicifolia lectin I and wheat germ agglutinin induced serum IgM Abs in mice that mediated the apoptosis of murine 4T1 and human MCF7 cell lines in vitro, paralleling the apoptotic activity of the lectins. Vaccine-induced anti-carbohydrate Abs reduced the outgrowth of micrometastases in the 4T1 spontaneous tumor model, significantly increasing survival time of tumor-bearing animals. This finding parallels suggestions that carbohydrate-reactive IgM with apoptotic activity may have merit in the adjuvant setting if the right carbohydrate-associated targets are identified.

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Section: Therapeutic Dna Immunization Arrested Liver Metastasismentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Reduction of Spontaneous Metastases through Induction of Carbohydrate Cross-Reactive Apoptotic Antibodies

Monzavi‐Karbassi

Artaud

Jousheghany

et al. 2005

The Journal of Immunology

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“…Although the benefits of multivalency are well established for both antibody and lectin binding to carbohydrates, the molecular mechanisms underlying these phenomena are poorly understood. Presumably, the effect is not attributable to the recognition of a combined epitope encompassing three or more sugar chains, as such a structure would exceed the size of an antibody-combining site (39). It is probable that multivalency contributes both to structural properties and entropy involved in binding (19).…”

Section: Binding Of Serum From Immunized Mice To Hiv-1 Iii-binfected mentioning

confidence: 99%

“…To identify likely residue types that can interact with ConA, we used the program LUDI. We have shown previously that LUDI could be used to structurally map the binding of peptide mimetics to the combining site of anti-carbohydrate antibodies (36,39). By using this approach, LUDI identified 153 interacting ligands for ConA, with some contacting the same sites as the pentasaccharide.…”

Section: Peptidyl Ligands That Bind To Cona-crystallographic Analysismentioning

confidence: 99%

Directing the Immune Response to Carbohydrate Antigens

Cunto-Amesty¹,

Dam²,

Luo³

et al. 2001

Journal of Biological Chemistry

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Peptide mimetics may substitute for carbohydrate antigens in vaccine design applications. At present, the structural and immunological aspects of antigenic mimicry, which translate into immunologic mimicry, as well as the functional correlates of each, are unknown. In contrast to screening peptide display libraries, we demonstrate the feasibility of a structure-assisted vaccine design approach to identify functional mimeotopes. By using concanavalin A (ConA), as a recognition template, peptide mimetics reactive with ConA were identified. Designed peptides were observed to compete with synthetic carbohydrate probes for ConA binding, as demonstrated by enzyme-linked immunosorbent assay and isothermal titration calorimetry (ITC) analysis. ITC measurements indicate that a multivalent form of one particular mimetic binds to ConA with similar affinity as does trimannoside. Splenocytes from mimeotope-immunized mice display a peptide-specific cellular response, confirming a T-cell-dependent nature for the mimetic. As ConA binds to the Envelope protein of the human immunodeficiency virus, type 1 (HIV-1), we observed that mimeotope-induced serum also binds to HIV-1-infected cells, as assessed by flow cytometry, and could neutralize T-cell line adapted HIV-1 isolates in vitro, albeit at low titers. These studies emphasize that mimicry is based more upon functional rather than structural determinants that regulate mimeotope-induced T-dependent antibody responses to polysaccharide and emphasize that rational approaches can be employed to develop further vaccine candidates.

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“…Structural mimicry has been suggested (but not demonstrated) for peptide and carbohydrate ligands of anti-Lewis Y MAb BR55-2, using molecular modeling (52), and proposed for a peptide mimic of the group B streptococcal type III capsular polysaccharide by Pincus and colleagues (53,54). However, structures of both peptide and carbohydrate with the cognate antibody are not available.…”

Section: Discussionmentioning

confidence: 99%

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.

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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...

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A Molecular Basis for Functional Peptide Mimicry of a Carbohydrate Antigen

Cited by 55 publications

References 44 publications

Reduction of Spontaneous Metastases through Induction of Carbohydrate Cross-Reactive Apoptotic Antibodies

Reduction of Spontaneous Metastases through Induction of Carbohydrate Cross-Reactive Apoptotic Antibodies

Directing the Immune Response to Carbohydrate Antigens

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

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