Synthetic Glycopeptide-Based Vaccines

Warren, Joel; Geng, Xu; Danishefsky, Samuel J.

doi:10.1007/128_031

Cited by 34 publications

(17 citation statements)

References 113 publications

(111 reference statements)

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“…During our studies of on-resin convergent synthesis of N-linked glycopeptides, reported in reference 6, we discovered that coupling of the large high mannose glycosylamine Man 8 GlcNAc 2 NH 2 1 to the free side chains of resin bound Fmoc-Asp and Fmoc-Glu resulted in excellent glycosylation yields. 20 On-resin glycosylation yields can be influenced by several factors including resin type, coupling reagents and solvents, and peptide structure.…”

Section: Resultsmentioning

confidence: 99%

“…4–6 In order to fulfill these complex functions nature endows N-linked glycans with enormous structural diversity, thereby creating significant challenges in the study of their structure and function. In addition to these challenges, N-linked glycans, like most carbohydrates, lack good chromophores that can be used as biophysical probes, and are often involved in weak multivalent interactions making it desirable to study carbohydrate multimers instead of monomers.…”

Section: Introductionmentioning

confidence: 99%

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Versatile on-resin synthesis of high mannose glycosylated asparagine with functional handles

Chen¹,

Pawlicki²,

Tolbert³

2014

Carbohydrate Research

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Here we present a synthetic route for solid phase synthesis of N-linked glycoconjugates containing high mannose oligosaccharides which allows the incorporation of useful functional handles on the N-terminus of asparagine. In this strategy, the C-terminus of an Fmoc protected aspartic acid residue is first attached to a solid phase support. The side chain of aspartic acid is protected by a 2-phenylisopropyl protecting group, which allows selective deprotection for the introduction of glycosylation. By using a convergent on-resin glycosylamine coupling strategy, an N-glycosidic linkage is successfully formed on the free side chain of the resin bound aspartic acid with a large high mannose oligosaccharide, Man8GlcNAc2, to yield N-linked high mannose glycosylated asparagine. The use of on-resin glycosylamine coupling provides excellent glycosylation yield, can be applied to couple other types of oligosaccharides, and also makes it possible to recover excess oligosaccharides conveniently after the on-resin coupling reaction. Useful functional handles including an alkene (p-vinylbenzoic acid), an alkyne (4-pentynoic acid), biotin, and 5-carboxyfluorescein are then conjugated onto the N-terminal amine of asparagine on-resin after the removal of the Fmoc protecting group. In this way, useful functional handles are introduced onto the glycosylated asparagine while maintaining the structural integrity of the reducing end of the oligosaccharide. The asparagine side chain also serves as a linker between the glycan and the functional group and preserves the native presentation of N-linked glycan which may aid in biochemical and structural studies. As an example of a biochemical study using functionalized high mannose glycosylated asparagine, a fluorescence polarization assay has been utilized to study the binding of the lectin Concanavalin A (ConA) using 5-carboxyfluorescein labeled high mannose glycosylated asparagine.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Versatile on-resin synthesis of high mannose glycosylated asparagine with functional handles

Chen¹,

Pawlicki²,

Tolbert³

2014

Carbohydrate Research

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“…Steps toward solving a major limitation of conventional synthetic strategies-the insufficiently small amount of material obtained-are being taken by automated [249]. (e) Installation of a phenyl-containing neo-TACA into ganglioside GM3 by metabolic glycoengineering (see Fig.…”

Section: Carbohydrate Antigensmentioning

confidence: 99%

“…A refinement of this technique is exemplified by multimeric antigenic constructs that target prostate and breast cancers with multiple TACA on the same molecular contruct (Fig. 1.10d) [249,258].…”

Section: Carbohydrate Antigensmentioning

confidence: 99%

Glycobiology and Immunology

Aich

Yarema

2008

Carbohydrate‐Based Vaccines and Immunotherapies

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“…This review has summarized the recent (in the past two to three years) efforts for overcoming these problems and for the development of TACA-based cancer vaccines. Several recent reviews have covered different aspects in the area [8-11]. …”

Section: Introductionmentioning

confidence: 99%

Recent development in carbohydrate-based cancer vaccines

Guo

Wang

2009

Current Opinion in Chemical Biology

140

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Summary Tumor-associated carbohydrate antigens (TACAs) are important molecular markers on the cancer cell surface, useful for the development of therapeutic cancer vaccines or cancer immunotherapies. However, due to their poor immunogenicity and/or immunotolerance, most TACAs fail to induce T cell-mediated immunity that is critical for cancer therapy. This review summarizes the recent effort to overcome this problem via constructing TACA conjugates with improved immunogenicity, such as by covalently coupling TACAs to proper carrier molecules to form clustered or multi-epitopic conjugate vaccines, coupling TACAs to a T cell peptide epitope and/or an immunostimulant epitope to form fully synthetic multi-component glycoconjugate vaccines, and developing vaccines based on chemically modified TACAs, which is combined with metabolic engineering of cancer cells.

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Synthetic Glycopeptide-Based Vaccines

Cited by 34 publications

References 113 publications

Versatile on-resin synthesis of high mannose glycosylated asparagine with functional handles

Versatile on-resin synthesis of high mannose glycosylated asparagine with functional handles

Glycobiology and Immunology

Recent development in carbohydrate-based cancer vaccines

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