Effect of PEGylation on Receptor Anchoring and Steric Shielding at Interfaces: An Adhesion and Surface Plasmon Resonance Study with Precision Polymers

Abstract

This study aims at quantifying the steric shielding effect of multivalent glycoconjugates targeting pathogens by blocking their carbohydrate binding sites. Specifically, PEGylated and non-PEGylated glycoconjugates are studied as inhibitors of lectins and bacterial adhesins evaluating the steric repulsion effect of the nonbinding PEG chains. We use the soft colloidal probe (SCP) adhesion assay to monitor the change in the adhesion energy of mannose (Man)decorated hydrogel particles on a layer of concanavalin A (ConA) in the presence of sequence-defined multivalent glycoconjugate inhibitors over time. The results show that PEGylated glycoconjugates achieve a stronger adhesion inhibition when compared to non-PEGylated glycoconjugates although the dissociation constants (K D ) of the PEGgylated compounds to ConA were larger. These results appear in line with Escherichia coli adhesion inhibition assays showing a small increase of bacteria detachment by PEGgylated glycoconjugates compared to non-PEGylated compounds. This suggests that an increase of sterical shielding via PEGylation may help reduce the invasiveness of pathogens even after they have adhered. Adhesion studies based on electrostatic interactions using amine-linked PEG of varying molecular weight confirm that such sterical shielding effect is not limited to carbohydrate-mediated adhesion.

Steric Shielding of cRGD-Functionalized Nanoparticles from Premature Exposition to Off-Target Endothelial Cells under a Physiological Flow

“…The abovementioned shielding concept itself is based on a steric hindrance effect that has been described by a multitude of previous studies. , It relies on the scalable introduction of longer, carboxylic acid terminated poly­(ethylene glycol) (PEG) chains into the surface of ligand-carrying polymeric NPs. To that end, integrin-targeting cRGD tethered to a shorter 2 kDa (2k) PEG chain was shielded with different amounts (25–75%) of either 3.5 or 5 k PEG chains.…”

PEGylated sequence-controlled macromolecules using supramolecular binding to target the Taspase1/Importin α interaction

“…This design is thus based on the general concept of sterical shielding for multivalent ligands to achieve inhibition. [3,23] For the first segment, we employ the previously established synthesis of sequence-controlled macromolecules ( Figure 1A). [24,25] Via the stepwise addition on solid support, a monodisperse, sequence-controlled scaffold is assembled and used for site selective attachment of GCP motifs.…”

Lectin and E. coli Binding to Carbohydrate-Functionalized Oligo(ethylene glycol)-Based Microgels: Effect of Elastic Modulus, Crosslinker and Carbohydrate Density

“…A new class of carbohydrate-based drugs inhibiting the anchorage of the pathogens to the glycocalyx have been shown to prevent and cure infections without inducing antibiotic resistance [15][16][17][18][19]. Potent inhibitors of carbohydrate-mediated pathogen adhesion are usually based on multivalent macromolecular glycoconjugates presenting many carbohydrate subunits, thus binding to bacterial lectins with high avidity [20][21][22][23][24][25].…”

“…The effect of these parameters on carbohydrate binding capabilities was determined by capturing ConA using microgel dispersions and observing the mobility of E. coli on thin microgel films (Figure 1). on multivalent macromolecular glycoconjugates presenting many carbohydrate subunits, thus binding to bacterial lectins with high avidity [20][21][22][23][24][25]. Microgel scaffolds have recently been developed as a platform to study carbohydrate-lectin interactions and to capture carbohydrate-binding bacteria [26][27][28][29][30].…”