Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry

Abstract

Preparations of the highly-ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary neoglycopolymers of a-D-mannose and β-D-glucose residues were achieved via ring-opening metathesis polymerization. Isothermal titration calorimetry measurements of these synthetic neoglycopolymers with Concanavalin A, revealed that hetero-functional diantennary architectures bearing both a-mannose and non-binding β-glucose units, poly(Man-Glc), binds to Concanavalin A (Ka = 16.1 × 106 M−1) comparably to homofunctional diantennary neoglycopolymer (Ka = 30 × 106 M−1) bearing only a-mannose unit, poly(Man-Man). In addition, poly(Man-Glc) neoglycopolymer shows a nearly five-fold increasing in binding affinity compared to monoantennary neoglycopolymer, poly(Man). Although the exact mechanism for the high binding affinity of poly(Man-Glc) to Con A is unclear, we hypothesize that the α-mannose bound to Con A might facilitate interaction of β-glucose with the extended binding site of Con A due to the close proximity of β-glucose to α-mannose residues in the designed polymerizable scaffold.

Design, synthesis, and evaluation of heparan sulfate mimicking glycopolymers for inhibiting heparanase activity

“…16c Since the distance between HBD-1 and HBD-2 is about 25 Å (Figure S10), the [GlcNS(6S)α(1,4)GlcA] moiety was joined to the diethylene glycol-containing azide linker that could interact with heparanase’s catalytic site 19 and undergo a “click” reaction with an alkyne unit of a scaffold A (Figure 1). 17a We propose that the scaffold A ’s carboxylate group could interact with the positively charged residues of heparanase’s HBDs. Monomer 3 serves as a control to determine the effect of the carboxylate group on the binding.…”

“…We designed monomer 2 containing a polymerizable scaffold 17 and the [GlcNS(6S)α(1,4)GlcA] disaccharide unit (Figure 2), essential for heparanase recognition. 18 Monomer 2 will then undergo ring-opening metathesis polymerization (ROMP) to form glycopolymers that could mimic the multivalent nature of HS polysaccharides.…”

“…19 The monomers are endowed with a strained bicyclic ring that undergoes ROMP to generate the glycopolymers. 17 Incorporation of carbohydrate units onto ROMP polymers was first conceived by Kiessling. 16e ROMP based polymer systems were later explored by the Hsieh-Wilson group to generate [IdoAβ1,4)GlcNS]-functionalized polymers as anticoagulant heparin mimetics.…”

Regulation of Protein-Carbohydrate Interactions in Bacteria and Fungi

“…It has been recently indicated in biological systems that binding and cross-linking of multivalent carbohydrates with multivalent lectins depict a new paradigm for supramolecular assembly and signal transduction [35]. Also, it has been recently suggested via isothermal titration calorimetry measurements of synthetic neoglycopolymers with Concanavalin A, Con A that heterofunctional diantennary architectures containing both alphamannose and non-binding beta-glucose units, poly(Man-Glc) binds to Con A; that the alpha-mannose bound to Con A facilitate interaction of beta-glucose with the extended binding site of Con A as a result of the presenting proximity of beta-glucose to alpha-mannose residues in the synthetic polymerizable scaffold [36].…”

Design and statistical modeling of mannose-decorated dapsone-containing nanoparticles as a strategy of targeting intestinal M-cells

“…Among the C-type lectin receptors, there are some prototypes that recognize specific carbohydrates and certain endogenous glycoproteins, including mannose. 10,[14][15][16] Once recognized by mannose receptors, the M-cells increase the uptake process. 15,17 Besides its specific conjugation with the C-type lectin receptors, mannose has the additional advantage to act as a mucoadhesive, as it may enhance the residence time of drug substances in the gut.…”