Antifungal vaccines have recently engendered considerable excitement for counteracting the resurgence of fungal infections. In this context, β-glucan, which is abundantly expressed on all fungal cell surfaces, functionally necessary for fungi and immunologically active, is an attractive target antigen. Aiming at the development of effective antifungal vaccines based on β-glucan, a series of its oligosaccharide derivatives were designed, synthesized, and coupled with a carrier protein, keyhole limpet hemocyanin (KLH), to form new semi-synthetic glycoconjugate vaccines. In this paper, a convergent and effective synthetic strategy using pre-activation-based iterative glycosylation was developed for the designed oligosaccharides. The strategy can be widely useful for rapid construction of large oligo-β-glucans with shorter oligosaccharides as building blocks. The KLH conjugates of the synthesized β-glucan hexa-, octa-, deca- and dodecasaccharides were demonstrated to elicit high titers of antigen-specific total and IgG antibodies in mice, suggesting the induction of functional T cell-mediated immunity. Moreover, it was revealed that octa-, deca-, and dodeca-β-glucans were much more immunogenic than the hexamer, while the octamer was the best. The results suggested that the optimal oligosaccharide sequence of β-glucan required for exceptional immunogenicity was a hepta- or octamer and that longer glucans are not necessarily better antigens, a finding that may be of general importance. Most importantly, the octa-β-glucan-KLH conjugate provoked protective immunities against Candida albicans infection in a systemic challenge model in mice, suggesting the great potential of this glycoconjugate as a clinically useful immunoprophylactic antifungal vaccine.

β-Glucans are important carbohydrate antigens on the surface of fungal cells useful for antifungal vaccine development. This paper has described a highly convergent and efficient strategy for the synthesis of structurally defined branched β-glucan oligosaccharides that can be used for detailed studies of β-glucans and for the design of β-glucan-based vaccines. The strategy was highlighted by assembling the title compounds via preactivation-based glycosylation with thioglycosides as glycosyl donors. It was used to successfully prepare β-glucan oligosaccharides that had a β-1,3-linked nonaglucan backbone with β-1,6-glucotetraose, β-1,3-glucodiose and β-1,3-glucotetraose branches at the 6-O-position of the nonaglucan central sugar unit. The structure and size of the glycosyl donors and acceptors used in the syntheses did not significantly affect the glycosylation efficiency, suggesting that the strategy can be generally useful for the synthesis of more complex structures.

The first total synthesis of a glycosylphosphatidylinositol (GPI) anchor bearing a polyunsaturated arachidonoyl fatty acid is reported. This lipid is found in mammalian GPIs that do not undergo lipid remodeling, a process that has important implications in the localization and function of GPI-anchored proteins. Incorporation of this oxidation- and reduction-sensitive lipid in the target GPI was accomplished using the para-methoxybenzyl (PMB) group for permanent hydroxyl group protection, which featured a selective, rapid, and efficient global deprotection protocol. The flexibility of this synthetic strategy was further highlighted by the inclusion of two additional GPI core structural modifications present in the GPI anchor of the human lymphocyte CD52 antigen.

[Chemical reaction: see text] An elimination and stereoselective hydrogenation of alpha-D-glucoheptonic-gamma-lactone derivative has been applied to prepare a differentially protected anti,anti-1,3,5-triol system, the utility of which has been extended for the total synthesis of anti-fungal 1,3-polyol/alpha-pyrone natural products.

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