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 IC
50
.
Correction for ‘Rapid sodium periodate cleavage of an unnatural amino acid enables unmasking of a highly reactive α-oxo aldehyde for protein bioconjugation’ by Robin L. Brabham et al., Org. Biomol. Chem., 2020, 18, 4000–4003, DOI: 10.1039/D0OB00972E.
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