Sequence‐Defined Introduction of Hydrophobic Motifs and Effects in Lectin Binding of Precision Glycomacromolecules

Abstract

This study investigates the influence of an increasingly hydrophobic backbone of multivalent glycomimetics based on sequence‐defined oligo(amidoamines) on their resulting affinity toward bacterial lectins. Glycomacromolecules are obtained by stepwise assembly of tailor‐made building blocks on solid support, using both hydrophobic aliphatic and aromatic building blocks to enable a gradual change in hydrophobicity of the backbone. Their binding behavior toward model lectin Concanavalin A (ConA) is evaluated using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) showing higher affinities for glycomacromolecules with higher content of hydrophobic and aromatic moieties in the backbone. Finally, glycomacromolecules are tested in a bacterial adhesion inhibition study against Escherichia coli where more hydrophobic backbones yield higher inhibitory potentials most likely due to additional secondary interactions with hydrophobic regions of the protein receptor as well as a change in conformation exposing carbohydrate ligands for increased binding. Overall, the results highlight the influence and thereby importance of the polymer backbone itself on the resulting properties of polymeric biomimetics.

Targeting Galectins With Glycomimetics

“…Second, flexibility can also be advantageous because the linker might adopt the proper conformation for favorable interactions to take place (Shewmake et al, 2008 ; Hevey, 2019 ). Third, the chemical nature of the linker is also relevant, since it might establish additional interactions with secondary binding sites and therefore improve the affinity (Boden et al, 2019 ). Undoubtedly, the choice of the ligand is a key factor in the outcome as well as its actual concentration within the scaffold.…”

Synthesis of Porphyrin and Bacteriochlorin Glycoconjugates through CuAAC Reaction Tuning

“…To evaluate the potential use of this methodology for the conjugation of more complex carbohydrate structures, the synthesis of a porphyrin‐based glycoconjugate was performed completely on solid support. Today complex oligosaccharides, as well as glycomimetics, are often synthesized on solid support . In addition, several examples exist in the literature where porphyrins have been synthesized using solid‐supported strategies .…”

Synthesis and self-assembly of amphiphilic precision glycomacromolecules

“…Synthesis of all APGs followed previously established protocols of solid phase polymer synthesis. 18 In short, for APG 1-4, 6 and 8, coupling of building blocks on a glycine preloaded Tentagel® resin was performed using benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as activation reagent and five equivalents of building block. For APG 5 and 7, a Tentagel® S RAM resin was used.…”

“…15,16 These molecules have been shown to mimic the multivalent binding of natural oligosaccharides or glycoconjugates such as the glycopeptides but offer the potential to introduce additional functionality such as light switchability or secondary binding motifs. [17][18][19] Furthermore, we could show that precision glycomacromolecules can be used in a bottom-up approach giving access to high molecular weight materials e.g. through polyaddition or grafting-to strategies.…”