Abstract
Galectin inhibitor design is an emerging research field due to the involvement of galectins in cancer. Galectin-3, in particular, plays an important role in tumor progression. To generate inhibitors, modifications of the glycan structure can be introduced. Conjugation of hydrophobic compounds to saccharides has proven to be promising as increased binding of galectin-3 can be observed. In the present study, we report on neo-glycans carrying hydrophobic biotin as novel ligands for human galectin-3. We modified N-acetyllactosamine- and N,N-diacetyllactosamine-based tetrasaccharides at the C6-position of the terminal saccharide unit using selective enzymatic oxidation and subsequent chemical conjugation of biotinamidohexanoic acid hydrazide. These neo-glycans were much better bound by galectin-3 than the unmodified counterparts. High selectivity for galectin-3 over galectin-1 was also proven. We generated multivalent neo-glycoproteins by conjugation of neo-glycans to bovine serum albumin showing high affinity for galectin-3. Compared to non-biotinylated neo-glycoproteins, we achieved high binding levels of galectin-3 with a lesser amount of conjugated neo-glycans. Multivalent ligand presentation of neo-glycoproteins significantly increased the inhibitory potency towards galectin-3 binding to asialofetuin when compared to free monovalent glycans. Our findings show the positive impact of 6-biotinylation of tetrasaccharides on galectin-3 binding, which broadens the recent design approaches for producing high-affinity ligands.
Highlights
Cell-surface-bound glycans mediate the interactions and communication between cells and their microenvironment [1,2,3,4]
We report on neo-glycans carrying hydrophobic biotin as novel ligands for human galectin-3
We further investigated competitive inhibition of galectin-3 binding to ASF by 6-biotinylated tetrasaccharides
Summary
Cell-surface-bound glycans mediate the interactions and communication between cells and their microenvironment [1,2,3,4]. Specialized proteins called lectins mediate the recognition and decoding of the glycan code presented by the cells [5]. Binding affinity of lectins toward their glycan ligand is rather low. It is dramatically increased by multivalent presentation of glycans in close proximity to each other, like nature does on glycolipids or glycoproteins [6]. These scaffolds bear multiple glycosylation sites or branched glycans. Arrangement in lipid rafts increases the multivalency, as well [7]
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