期刊
JACS AU
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacsau.2c00312
关键词
biorthogonal; conjugation; glycosylation; glycoprotein; bacterial toxin
资金
- U.K. Engineering and Physical Sciences Research Council [1799721]
- Biotechnology and Biological Research Council [BB/M011151/1]
- Wellcome Trust [097827/Z/11/A, WT094232MA, 094232/Z/10/Z, 109154/Z/15/A]
- Iceni Diagnostics
- Wellcome Trust [109154/Z/15/A, 094232/Z/10/Z, 097827/Z/11/A] Funding Source: Wellcome Trust
This study presents a site-specific bioorthogonal approach for synthesizing homogeneous glycoproteins. By developing a bifunctional bioorthogonal linker and functionalizing reducing sugars and glycan derivatives, synthetic neoglycoproteins were successfully produced as inhibitors of cholera toxin, demonstrating the potential of this method for creating homogeneous glycoproteins.
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.
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