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The Evolution of a Glycoconjugate Vaccine for Candida albicans

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Carbohydrates as Drugs

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 12))

Abstract

The monoclonal antibody C3.1 has been found to afford protection against Candida albicans, an opportunistic fungal pathogen. The exceptional inhibition profile of C3.1 has propelled synthetic and immunochemical studies of antibody–oligosaccharide interactions, leading to the development of candidate vaccines. The β1,2-linked mannan of the fungal-cell-wall phosphomannan complex is a protective antigen that exhibits a well-defined conformation. A β1,2-linked trisaccharide conjugated to tetanus toxoid generates protective antibodies in rabbits, and STD-NMR studies show that these antibodies approximate the binding profile of the protective monoclonal antibody. This simple trisaccharide–tetanus toxoid conjugate was a strong immunogen in rabbits, but it was poorly immunogenic in mice. However, when a carbohydrate antigen targeted at dendritic cells was incorporated in this conjugate vaccine, it improved uptake and processing of the antigen and resulted in a five-fold higher mannan-specific antibody response together with a cytokine profile appropriate for an antifungal vaccine. When the same trisaccharide was conjugated to a T-cell peptide derived from Candida cell-wall protein, the resulting glycopeptide–tetanus toxoid conjugate engendered a peptide- and carbohydrate-specific response that afforded protection against live challenge by C. albicans without requiring an adjuvant.

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Abbreviations

Abe:

Abequose (3,6-dideoxy-d-xylo-hexose)

Ac:

Acetyl

All:

Allyl

′Bn:

Benzyl

Boc:

tert-Butoxycarbonyl

BSA:

Bovine serum albumin

Bu:

Butyl

DMF:

Dimethylformamide

DMSO:

Dimethyl sulfoxide

Enol:

Enolase

Fab:

Fragment (of an antibody) that contains the antigen-binding region

Fba:

Fructose-bisphosphate aldolase

Gal:

Galactose

Gap1:

Glyceraldehyde-3-phosphate dehydrogenase

Glc:

Glucose

GlcNAc:

N-acetylglucosamine

Hwp1:

Hyphal wall protein-1

IC50 :

Half-maximal inhibitory concentration

LPS:

Lipopolysaccharide

mAb:

Monoclonal antibody

Man:

Mannose

Me:

Methyl

Met6:

Methyltetrahydropteroyltriglutamate

NOE:

Nuclear Overhauser effect (NMR)

Pgk1:

Phosphoglycerate kinase 1

Pr:

Propyl

Rha:

Rhamnose

STD-NMR:

Saturation transfer difference nuclear magnetic resonance

t-Bu:

tert-Butyl

Tf:

Trifluoromethanesulfonyl (triflyl)

THF:

Tetrahydrofuran

TMSOTf:

Trimethylsilyl trifluoromethanesulfonate

Tr:

Triphenylmethyl (trityl)

trNOE:

Transferred nuclear Overhauser effect (NMR)

T-ROESY:

Two-dimensional rotating-frame Overhauser effect spectroscopy

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  1. Department of Chemistry, Alberta Glycomics Centre, University of Alberta, Edmonton, AB, Canada, T6G 2G2

    David R. Bundle

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  1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

    Peter H. Seeberger

  2. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

    Christoph Rademacher

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Bundle, D.R. (2014). The Evolution of a Glycoconjugate Vaccine for Candida albicans . In: Seeberger, P., Rademacher, C. (eds) Carbohydrates as Drugs. Topics in Medicinal Chemistry, vol 12. Springer, Cham. https://doi.org/10.1007/7355_2014_60

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