Direct Enzymatic Branch‐End Extension of Glycocluster‐Presented Glycans: An Effective Strategy for Programming Glycan Bioactivity

The sequence of a glycan and its topology of presentation team up to determine the specificity and selectivity of recognition by saccharide receptors (lectins). Structure–activity analysis would be furthered if the glycan part of a glycocluster could be efficiently elaborated in situ while keeping all other parameters constant. By using a bacterial α2,6‐sialyltransferase and a small library of bi‐ to tetravalent glycoclusters, we illustrate the complete conversion of scaffold‐presented lactoside units into two different sialylated ligands based on N ‐acetyl/glycolyl‐neuraminic acid incorporation. We assess the ensuing effect on their bioactivity for a plant toxin, and present an analysis of the noncovalent substrate binding contacts that the added sialic acid moiety makes to the lectin. Enzymatic diversification of a scaffold‐presented glycan can thus be brought to completion in situ, offering a versatile perspective for rational glycocluster engineering.