Selective and Tunable Galectin Binding of Glycopolymers Synthesized by a Generalizable Conjugation Method

Abstract

Glycopolymers, conjugates of synthetic polymers with pendant carbohydrates, are becoming increasingly important to probe the role of carbohydrates in cellular processes and for applications like biosensors and drug delivery. A library of glycopolymers bearing different sugar moieties was synthesized by grafting amino-functionalized sugars to poly(acrylic acid) via DMTMM coupling. Primary amines were introduced at the anomeric (C-1) position to a number of unprotected mono-, di-, and trisaccharides using ammonium carbamate and conjugated to poly(acrylic acid) of different molecular weights, synthesized by reversible addition−fragmentation chain transfer (RAFT) polymerization. This approach provides a simple and efficient route for the preparation of glycopolymers that differ only in the identity or degree of substitution of the sugar moiety on the polymer. The binding parameters (k a , k d , and K D ) of these new glycopolymers to galectins-1 and -3 were quantified using surface plasmon resonance. The galectins selectively bound only to lactose-containing polymers, and the binding affinity was dependent on the galectin type, degree of sugar substitution and the molecular weight of polymer chains. Binding to both galectin-1 and -3 increased with a higher degree of sugar substitution, and higher molecular weight of the polymer backbone, reaching K D values on the order of 10 −11 M.

Polymer‐Based Drug‐Free Therapeutics for Anticancer, Anti‐Inflammatory, and Antibacterial Treatment

“…This effect, called the “cluster glycoside effect” or “multivalent effect,” [ 65–67 ] results in multivalent carbohydrate−protein interactions, which enhance the protein association constants and promote a stronger affinity of lectins toward their multivalent glyco‐ligand as compared to the corresponding monovalent ligand. [ 55,60,68–74 ] Therefore, many research groups are attracted to the investigation of polymers as ideal constructs that can mimic natural saccharide ligands and promote higher activities on the basis of an increase in the available binding sites and efficient glycan‐based interactions (see Figure 2 ). [ 55,59–61,69,74,75 ]…”

“…Nevertheless, the present review focuses on synthetic glycopolymers that are defined as synthetic macromolecules with pendant mono and/or oligosaccharide moieties. [ 55,59,61,69,70,74,75,92,93 ] Currently, there are two synthetic approaches for the production of well‐defined synthetic glycopolymers. [ 61,70,74,92,93 ] The first strategy relies on the “direct polymerization” approach of carbohydrate‐substituted monomers, the so‐called glycomonomers, as the sugar source.…”

“…[ 55,59,61,69,70,74,75,92,93 ] Currently, there are two synthetic approaches for the production of well‐defined synthetic glycopolymers. [ 61,70,74,92,93 ] The first strategy relies on the “direct polymerization” approach of carbohydrate‐substituted monomers, the so‐called glycomonomers, as the sugar source. [ 55,59,61,92,93 ] This approach frequently involves complicated procedures for the synthesis of these glycomonomers, as some of them tend to self‐polymerize during the purification procedures.…”

“…These drawbacks make this method synthetically challenging and time‐consuming. [ 59,61,70,92 ] Additionally, because of the likely loss of the monomers during the polymerization processes, the use of rare and expensive sugar ligands will be the limiting point in this case. [ 95 ] The second strategy relies on the attachment of previously functionalized carbohydrates to polymer carriers or scaffolds bearing reactive functional groups, so‐called “postpolymerization approach,” applying numerous different chemistries, i.e., Huisgen's cycloaddition between azides and alkynes, [ 96 ] coupling thiol−ene [ 97 ] “click” reactions, or amine‐carboxylic acid coupling reactions.…”

“…[ 95 ] The second strategy relies on the attachment of previously functionalized carbohydrates to polymer carriers or scaffolds bearing reactive functional groups, so‐called “postpolymerization approach,” applying numerous different chemistries, i.e., Huisgen's cycloaddition between azides and alkynes, [ 96 ] coupling thiol−ene [ 97 ] “click” reactions, or amine‐carboxylic acid coupling reactions. [ 55,70,92,95,98 ] Even though the second strategy does not lead to 100% functionalization, resulting in a non‐homogeneous glycan presentation along the polymer chain, [ 93 ] it allows the production of the libraries of glycopolymers with the same macromolecular characteristics, such as the degree of polymerization, macromolecular structure, and dispersity. [ 94 ]…”