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Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans.

ABSTRACT: Synthetic cell-surface glycans are promising vaccine candidates against Clostridium difficile. The complexity of large, highly antigenic and immunogenic glycans is a synthetic challenge. Less complex antigens providing similar immune responses are desirable for vaccine development. Based on molecular-level glycan-antibody interaction analyses, we here demonstrate that the C. difficile surface polysaccharide-I (PS-I) can be resembled by multivalent display of minimal disaccharide epitopes on a synthetic scaffold that does not participate in binding. We show that antibody avidity as a measure of antigenicity increases by about five orders of magnitude when disaccharides are compared with constructs containing five disaccharides. The synthetic, pentavalent vaccine candidate containing a peptide T-cell epitope elicits weak but highly specific antibody responses to larger PS-I glycans in mice. This study highlights the potential of multivalently displaying small oligosaccharides to achieve antigenicity characteristic of larger glycans. The approach may result in more cost-efficient carbohydrate vaccines with reduced synthetic effort.

SUBMITTER: Broecker F

PROVIDER: S-EPMC4838876 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans.

Broecker Felix F Hanske Jonas J Martin Christopher E CE Baek Ju Yuel JY Wahlbrink Annette A Wojcik Felix F Hartmann Laura L Rademacher Christoph C Anish Chakkumkal C Seeberger Peter H PH

Nature communications 20160419

Synthetic cell-surface glycans are promising vaccine candidates against Clostridium difficile. The complexity of large, highly antigenic and immunogenic glycans is a synthetic challenge. Less complex antigens providing similar immune responses are desirable for vaccine development. Based on molecular-level glycan-antibody interaction analyses, we here demonstrate that the C. difficile surface polysaccharide-I (PS-I) can be resembled by multivalent display of minimal disaccharide epitopes on a sy ...[more]

PMID: 27091615

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Project description:Multivalent lectin-glycan interactions (MLGIs) are widespread and vital for biology, making them attractive therapeutic targets. Unfortunately, the structural and biophysical mechanisms of several key MLGIs remain poorly understood, limiting our ability to design spatially matched glycoconjugates as potential therapeutics against specific MLGIs. We have recently demonstrated that natural oligomannose-coated nanoparticles are powerful probes for MLGIs. They can provide not only quantitative affinity and binding thermodynamic data but also key structural information (e.g, binding site orientation and mode) useful for designing glycoconjugate therapeutics against specific MLGIs. Despite success, how designing parameters (e.g., glycan type, density, and scaffold size) control their MLGI biophysical and antiviral properties remains to be elucidated. A synthetic pseudodimannose (psDiMan) ligand has been shown to selectively bind to a dendritic cell surface tetrameric lectin, DC-SIGN, over some other multimeric lectins sharing monovalent mannose specificity but having distinct cellular functions. Herein, we display psDiMan polyvalently onto gold nanoparticles (GNPs) of varying sizes (e.g., ∼5 and ∼13 nm, denoted as G5- and G13 psDiMan hereafter) to probe how the scaffold size and glycan display control their MLGI properties with DC-SIGN and the closely related lectin DC-SIGNR. We show that G5/13 psDiMan binds strongly to DC-SIGN, with sub-nM K ds, with affinity being enhanced with increasing scaffold size, whereas they show apparently no or only weak binding to DC-SIGNR. Interestingly, there is a minimal, GNP-size-dependent, glycan density threshold for forming strong binding with DC-SIGN. By combining temperature-dependent affinity and Van't Hoff analyses, we have developed a new GNP fluorescence quenching assay for MLGI thermodynamics, revealing that DC-SIGN-Gx-psDiMan binding is enthalpy-driven, with a standard binding ΔH 0 of ∼ -95 kJ mol-1, which is ∼4-fold that of the monovalent binding and is comparable to that measured by isothermal titration calorimetry. We further reveal that the enhanced DC-SIGN affinity with Gx-psDiMan with increasing GNP scaffold size is due to reduced binding entropy penalty and not due to enhanced favorable binding enthalpy. We further show that DC-SIGN binds tetravalently to a single Gx-psDiMan, irrespective of the GNP size, whereas DC-SIGNR binding is dependent on GNP size, with no apparent binding with G5, and weak cross-linking with G13. Finally, we show that Gx-psDiMans potently inhibit DC-SIGN-dependent augmentation of cellular entry of Ebola pseudoviruses with sub-nM EC50 values, whereas they exhibit no significant (for G5) or weak (for G13) inhibition against DC-SIGNR-augmented viral entry, consistent to their MLGI properties with DC-SIGNR in solution. These results have established Gx-psDiMan as a versatile new tool for probing MLGI affinity, selectivity, and thermodynamics, as well as GNP-glycan antiviral properties.

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Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans.

Publications

Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans.

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