Glycopolymers are synthetic analogues of natural polysaccharides that connect saccharides through a synthetic backbone rather than through glycosidic bonds. Current glycopolymerization techniques can be used to create large quantities of material with good control over the saccharide identity and chain length of the polymer, which has allowed structure-property studies of glycopolymer binding with lectins. These studies have shown that structures with longer chain length exhibit greater binding with lectins. However, these studies have not fully addressed the effects of branching or spatial orientation on lectin binding.
Branching architecture affects the biological and physical properties of polysaccharides. Similarly, branching should also affect how glycopolymers interact with their target lectins, yet few reports of branched glycopolymers have been reported. Additionally, there have been no studies on the effect of placing saccharide residues in the polymer backbone and at the branch point. To address this limitation in current synthetic techniques, polymers with branching architecture that incorporate saccharide at the branch point have been synthesized via atom transfer radical polymerization of a saccharide (either mannose or galactose) inimer and mannose monomer. Branching architecture was confirmed through GPC-PMMA, GPC-LS, and mass spectrometry. These branched glycopolymers more fully recapitulate natural branched polysaccharide structures and were found to interact more strongly than linear glycopolymers with mannose binding lectin (MBL), an immune complement protein. Most significantly, mannose at the branch point increases the polymer's interaction with MBL compared to similar structures with galactose or no saccharide content at the branch point.
In addition to polysaccharides found throughout living systems, proteins are often post-translationally modified with polysaccharide chains to create glycoproteins. We hypothesized that mimicking the 3D spatial orientation of these glycans through polymerization of glycomonomers from a protein macroinitiator can result in different binding properties of the resulting conjugate. Bovine serum albumin was modified to present multiple initiator groups which initiated the polymerization of mannose and galactose monomers via atom transfer radical polymerization. MBL interaction increases with the number and density of mannose residues attached to the protein. 3D presentation of multiple polymer chains from a protein significantly enhances lectin interaction than compared to linear glycopolymer chains with the same number of mannoses but without 3D presentation.
Structure-property studies have also been hampered by the inherently different distributions in molecular weight between different glycopolymer samples. Post-polymerization modification of pyridyl disulfide polymers with thioglycosides was demonstrated as a route towards creating glycopolymers with pendant glycosides and uniform underlying architecture and polymer chain distribution. These polymers were used to study the effect of glycopolymers on fibroblast adhesion.
We have described synthetic techniques for creating biomimetic glycopolymers that narrow the gap between synthetic structures and natural polysaccharides while still maintaining the high throughput advantage of glycopolymerizations. The structure-property studies have shown how subtle changes in polymer branching architecture and 3D spatial orientation can lead to dramatic enhancements of lectin binding, and can be applied to improved designs of glycomimetic drugs.
