Enzyme‐linked immunosorbent assays and surface plasmon resonance studies are performed, revealing a positive impact of the sulfonated/sulfated nonglycosidic motifs on galectin‐3 binding but not on galectin‐1 binding. In this work, multivalency and the introduction of nonglycosidic motifs bearing either neutral, amine, or sulfonated/sulfated groups are used to better understand binding in the galectin‐3 CRD. Heteromultivalent precision glycomacromolecules have the potential to serve as ligands for galectins. Thus, research has focused on the design and synthesis of galectin‐targeting ligands for use as diagnostic markers or potential therapeutics. Galectins, a family of β‐galactoside‐binding proteins, are known to play crucial roles in different signaling pathways involved in tumor biology.
Within this work, a new class of sequence‐defined heteromultivalent glycomacromolecules bearing lactose residues and nonglycosidic motifs for probing glycoconjugate recognition in carbohydrate recognition domain (CRD) of galectin‐3 is presented. For example, Nilsson and co-workers have demonstrated that galactose monosaccharides functioned with aromatic moieties at the 3-O position can be selective, potent inhibitors of galectin-3, and that 3-substituted oxazoles could provide selectivity for galectin-3 over galectin-1. 38] Other studies using monovalent carbohydrates have revealed that the introduction of nonglycosidic moieties can enhance the affinity of ligands targeting galectin-3. This approach takes advantage of the ability of galectin-3 to oligomerize in the presence of multivalent ligands leading to an effective increase in binding avidity. One group of examples involves the multivalent presentation of carbohydrate residues on macromolecular scaffolds as described by Gabius et al., Roy et al., Nilsson et al., Wang et al., Argueso et al., Cloninger et al., Lecommandoux et al., Elling and co-workers, Percec et al., Putnam et al., and more recently Rosencrantz et al. These studies exposed the critical role of galectin-3's N-terminal domain in formation of galectin-3 multimers and also enabled comparisons of polymer templated aggregation using nonspecific interactions versus specific protein–carbohydrate binding interactions. Dynamic light scattering measurements revealed a direct correlation between the hydrodynamic radii of the lactose functionalized dPGs and the size of the galectin-3/lactose functionalized dPG aggregates formed upon mixing the lactose functionalized dPGs with galectin-3 in solution. These lactose functionalized dPGs were used to study the templated aggregation of galectin-3, a galactoside binding protein that is overexpressed during many processes involved in cancer progression.
#Multivalent protein scaffold series
A series of lactose functionalized dPGs bearing different densities of lactose functional groups was also synthesized. Here, we report the synthesis of a series of lactose functionalized dPGs with different hydrodynamic radii. The highly branched nature and high density of endgroups make the dPGs particularly attractive frameworks for the study of multivalent interactions such as multivalent protein–carbohydrate interactions. Dendritic polyglycerols (dPGs) are emerging as important polymers for the study of biological processes due to their relatively low toxicity and excellent biocompatibility.