Multivalent Presentation of Mannose on Hyperbranched Polyglycerol and their Interaction with Concanavalin A Lectin

Abstract

We describe the synthesis of multivalent mannose derivatives by using hyperbranched polyglycerols (hPG) as a scaffold with different linker structures. Grafting of protected mannose (Man) units is achieved by using Cu(I) -catalyzed Huisgen click chemistry with either an anomeric azide or propargyl ether onto complementarily functionalized alkyne or azido polymer surfaces. NMR spectroscopy, dynamic light scattering (DLS), IR spectroscopy, size-exclusion chromatography (SEC), and elemental analysis have been used to characterize the hPG-Man compounds. The surface availability and bioactivity of Man-modified polymers were evaluated by using a competitive surface plasmon resonance (SPR)-based binding assay by interactions of the glycopolymers with concanavalin A (Con A), a lectin that binds mannose containing molecules. The results indicated that the novel glycoarchitectures presented in this work are efficient inhibitors of Con A-mannose recognition and resulted in inhibitor concentrations (mean IC(50)) from the micro- to the nanomolar range, whereas the corresponding monovalent mannoside (methyl-Man) requires millimolar concentrations. The results provide an interesting structure-activity relationship for libraries of materials that differ in the linkage of the sugar moiety presented on a biocompatible polyglycerol scaffold.

Glycodendrimers and Modified ELISAs: Tools to Elucidate Multivalent Interactions of Galectins 1 and 3

“…Multivalent protein-carbohydrate interactions generally rely on multiple points of recognition/binding to enhance the individual binding interaction between one carbohydrate and its receptor, which are typically weak interactions [ 1 ]. A variety of synthetic multivalent scaffolds including linear polymers [ 2 , 3 , 4 ], star [ 5 , 6 , 7 ] and hyperbranched [ 8 , 9 , 10 ] polymers, gold nanoparticles [ 11 , 12 , 13 ], dendrimers [ 14 ], proteins [ 15 ], beads [ 16 ] and surfaces [ 17 , 18 , 19 , 20 ] have been functionalized with carbohydrates and then applied to the study and the mediation of multivalent protein-carbohydrate interactions [ 21 ]. These carbohydrate functionalized scaffolds have been used to study biological processes such as oncologic cellular aggregation [ 22 ] viral cell attachment [ 15 , 23 ], bacterial recognition [ 24 ], and signal transduction [ 25 ].…”

Enhanced Inhibition of Protein Carbohydrate Interactions by Dendritic Multivalent Glycoligands

“…The divalent 9 still showed a 19-fold enhancement ( Figure 2) (11), but the small PAMAM glycodendrimer 10, showed hardly any noticeable enhancement. In contrast, larger systems, such as the higher generation PAMAM glycodendrimer 11 showed a large multivalency enhancement per sugar of 660 fold (12,13) and similar observations were made for hyperbranched polyglycerol based glycodendrimers (14). These enhancements of larger systems are not limited to dendrimers since polymers, micelles, quantum dots, and linear glycopolymers were also shown to exhibit these effects (15,16).…”

Poly(triazolyl methacrylate) glycopolymers as potential targeted unimolecular nanocarriers

“…In nature carbohydrates are involved in the regulation of a plethora of biological processes such as cell differentiation, proliferation and adhesion, inflammation, and immunological response, 72 thus targeted drug delivery through sugar-binding receptors to modulate these key processes is particularly attractive. 73 Initially, an agglutination assay using mannose-binding concanavalin A model lectin 74,75 was developed, based on a protocol described by Haddleton and co-workers. 76 In the first part of the assay, increasing amounts of Con A were added to solutions of glycopolymer-Nile red complexes (obtained from 1.00 mg mL −1 of (1) MAN or (2) MAN and 20 µg mL −1 (63 µM) of Nile red), resulting in the formation of insoluble Con A-complex clusters.…”