Synthesis of multivalent glycopeptide conjugates that mimic an HIV epitope

Bailey, Jennifer K.; Nguyen, Dung N.; Horiya, Satoru; Krauss, Isaac J.

doi:10.1016/j.tet.2016.07.062

Cited by 13 publications

(15 citation statements)

References 32 publications

(30 reference statements)

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“…This “10V1S” mutant exhibited a 2G12 K D that was similar to 10V1 (SI, Table S1), and conjugation to the carrier protein proceeded well using methods that we have reported previously (Figure 2a). 47…”

Section: Resultsmentioning

confidence: 99%

Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities

Nguyen

Stanfield

et al. 2019

ACS Cent. Sci.

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Up to ∼20% of HIV-infected individuals eventually develop broadly neutralizing antibodies (bnAbs), and many of these antibodies (∼40%) target a region of dense high-mannose glycosylation on gp120 of the HIV envelope protein, known as the “high-mannose patch” (HMP). Thus, there have been numerous attempts to develop glycoconjugate vaccine immunogens that structurally mimic the HMP and might elicit bnAbs targeting this conserved neutralization epitope. Herein, we report on the immunogenicity of glycopeptides, designed by in vitro selection, that bind tightly to anti-HMP antibody 2G12. By analyzing the fine carbohydrate specificity of rabbit antibodies elicited by these immunogens, we found that they differ from some natural human bnAbs, such as 2G12 and PGT128, in that they bind primarily to the core structures within the glycan, rather than to the Manα1 → 2Man termini (2G12) or to the whole glycan (PGT128). Antibody specificity for the glycan core may result from extensive serum mannosidase trimming of the immunogen in the vaccinated animals. This finding has broad implications for vaccine design aiming to target glycan-dependent HIV neutralizing antibodies.

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Section: Resultsmentioning

confidence: 99%

Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities

Nguyen

Stanfield

et al. 2019

ACS Cent. Sci.

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“…To test the effect of antigen delivery kinetics on the anti-glycan response, we conducted rabbit immunizations with our g10F6 glycopeptide conjugated to CRM197 carrier protein, − administered in three different regimens (Figure ). In the control group, a standard bolus dose was tested at 4-week intervals.…”

Section: Resultsmentioning

confidence: 99%

“…The Env region most commonly targeted by bnAbs (∼40%) is the high-mannose patch (HMP, Figure a), a region of gp120 containing a dense array of N-linked glycosylation sites (N332, N339, N392, N295, N262, N448, N363) largely populated by Man 9/8 GlcNAc 2 glycans . bnAbs targeting this region bind to combinations of these glycans and conserved polypeptide residues (e.g., PGT121- and PGT128 bnAb families) − or exclusively to glycans (e.g., bnAb 2G12). , In all cases, these bnAb epitopes contain multiple glycans; thus, carbohydrate chemists have been very interested in the design and synthesis of carbohydrate clusters to mimic these epitopes. − In these epitope-focused vaccine strategies, it is reasoned that a glycopeptide or carbohydrate mimic of the HMP might elicit antibodies that bind the HMP and are broadly neutralizing (Figure a).…”

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confidence: 99%

The Impact of Sustained Immunization Regimens on the Antibody Response to Oligomannose Glycans

et al. 2020

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The high mannose patch (HMP) of the HIV envelope protein (Env) is the structure most frequently targeted by broadly neutralizing antibodies; therefore, many researchers have attempted to use mimics of this region as a vaccine immunogen. In our previous efforts, vaccinating rabbits with evolved HMP mimic glycopeptides containing Man9 resulted in an overall antibody response targeting the glycan core and linker rather than the full glycan or Manα1→2Man tips of Man9 glycans. A possible reason could be processing of our immunogen by host serum mannosidases. We sought to test whether more prolonged dosing could increase the antibody response to intact glycans, possibly by increasing the availability of intact Man9 to germinal centers. Here, we describe a study investigating the impact of immunization regimen on antibody response by testing immunogen delivery through bolus, an exponential series of mini doses, or a continuously infusing mini-osmotic pump. Our results indicate that, with our glycopeptide immunogens, standard bolus immunization elicited the strongest HIV Env-binding antibody response, even though higher overall titers to the glycopeptide were elicited by the exponential and pump regimens. Antibody selectivity for intact glycan was, if anything, slightly better in the bolus-immunized animals.

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“…These candidates were then synthesized in a larger scale using fast flow peptide synthesis with subsequent glycosylation of the alkyne-functionalized peptide backbone via ‘click’ glycosylation [95]. In fast flow peptide synthesis, all reagent solutions also including the activated amino acids are pumped through a heated reactor containing the SPPS resin, thus ensuring a continuous and fresh supply of reagents.…”

Section: Viral Infectionsmentioning

confidence: 99%

Glycopeptides and -Mimetics to Detect, Monitor and Inhibit Bacterial and Viral Infections: Recent Advances and Perspectives

Behren

Westerlind

2019

Molecules

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The initial contact of pathogens with host cells is usually mediated by their adhesion to glycan structures present on the cell surface in order to enable infection. Furthermore, glycans play important roles in the modulation of the host immune responses to infection. Understanding the carbohydrate-pathogen interactions are of importance for the development of novel and efficient strategies to either prevent, or interfere with pathogenic infection. Synthetic glycopeptides and mimetics thereof are capable of imitating the multivalent display of carbohydrates at the cell surface, which have become an important objective of research over the last decade. Glycopeptide based constructs may function as vaccines or anti-adhesive agents that interfere with the ability of pathogens to adhere to the host cell glycans and thus possess the potential to improve or replace treatments that suffer from resistance. Additionally, synthetic glycopeptides are used as tools for epitope mapping of antibodies directed against structures present on various pathogens and have become important to improve serodiagnostic methods and to develop novel epitope-based vaccines. This review will provide an overview of the most recent advances in the synthesis and application of glycopeptides and glycopeptide mimetics exhibiting a peptide-like backbone in glycobiology.

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Synthesis of multivalent glycopeptide conjugates that mimic an HIV epitope

Cited by 13 publications

References 32 publications

Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities

Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities

The Impact of Sustained Immunization Regimens on the Antibody Response to Oligomannose Glycans

Glycopeptides and -Mimetics to Detect, Monitor and Inhibit Bacterial and Viral Infections: Recent Advances and Perspectives

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