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Bioorthogonal, Bifunctional Linker for Engineering Synthetic Glycoproteins

McBerney, Ryan; Dolan, Jonathan; E. Cawood, Emma; E. Webb, Michael; Bruce Turnbull, W.

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Authors

Ryan McBerney

Emma E. Cawood

Michael E. Webb

W. Bruce Turnbull



Abstract

Post-translational glycosylation of proteins results in complex mixtures of heterogeneous protein glycoforms. Glycoproteins have many potential applications from fundamental studies of glycobiology to potential therapeutics, but generating homogeneous recombinant glycoproteins using chemical or chemoenzymatic reactions to mimic natural glycoproteins or creating homogeneous synthetic neoglycoproteins is a challenging synthetic task. In this work, we use a site-specific bioorthogonal approach to produce synthetic homogeneous glycoproteins. We develop a bifunctional, bioorthogonal linker that combines oxime ligation and strain-promoted azide–alkyne cycloaddition chemistry to functionalize reducing sugars and glycan derivatives for attachment to proteins. We demonstrate the utility of this minimal length linker by producing neoglycoprotein inhibitors of cholera toxin in which derivatives of the disaccharide lactose and GM1os pentasaccharide are attached to a nonbinding variant of the cholera toxin B-subunit that acts as a size- and valency-matched multivalent scaffold. The resulting neoglycoproteins decorated with GM1 ligands inhibit cholera toxin B-subunit adhesion with a picomolar IC50.

Journal Article Type Article
Acceptance Date Aug 15, 2022
Publication Date Aug 26, 2022
Publicly Available Date Mar 28, 2024
Journal JACS Au
Print ISSN 2691-3704
Publisher American Chemical Society
DOI https://doi.org/10.1021/jacsau.2c00312
Publisher URL https://pubs.acs.org/doi/10.1021/jacsau.2c00312

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