Glycodendriproteins:  A Synthetic Glycoprotein Mimic Enzyme with Branched Sugar-Display Potently Inhibits Bacterial Aggregation

Abstract

The continuing ability of bacteria to resist current antibiotic treatments highlights the need for alternative strategies for inhibiting their pathogenicity. Bacterial attachment is a major factor in infectivity and virulence. This key binding phase of bacteria to any potential host is mediated by adhesin proteins and so these present an attractive therapeutic target for antiinfective blocking strategies. However, the natural ligands to adhesins are large, typically complex molecules that are difficult to mimic with small molecules. We describe here a method that creates precise synthetic mimics of glycoproteins that are designed to bind adhesins. By using protein-degrading enzymes as the basis for these mimics we have created large-molecule protein ligands that inhibit aggregation of pathogenic bacteria at levels greater than a million-fold higher than small-molecule inhibitors of adhesins.

Probing multivalent carbohydrate–lectin interactions by an enzyme-linked lectin assay employing covalently immobilized carbohydrates

“…[30][31][32][33][34] Microtiter plates are coated with a reference ligand (often a (neo)glycoprotein or polysaccharide) and IC 50 values for inhibition of the binding of an enzyme-labeled lectin to the immobilized reference ligand (the matrix) by the soluble ligands to be tested are determined. The advantage of ELLA compared to solid-phase binding assays such as surface plasmon resonance (SPR) 35 is that both, lectin and ligand are in solution.…”

Protein–polymer therapeutics: a macromolecular perspective

“…95 Davis' group showed that the attachment of a carbohydrate based dendron onto a glycoprotein protease facilitated the anchoring of the hybrid construct onto bacterial cell surfaces. 96 Subsequent cleavage of the membrane proteins by the glycoprotein protease inhibited the infectivity of the bacteria, Actinomyces naeslundii, with an IC 50 = 20 nM. 96 Through this approach, dendronized proteins emerged as a novel class of hybrid materials exhibiting synergistic biological properties while simultaneously maintaining molecular definition.…”

Merging Organic and Polymer Chemistries to Create Glycomaterials for Glycomics Applications

“…[30] Dendrimers show great promise for applications in therapeutic processes since they can adopt a protein-like structure and thus mimic the branched carbohydrates of natural glycoproteins. [31] Such glycosylation techniques, performed by step growth condensation strategies, may help to overcome problems associated with heterogenous glycoproteins synthesis. [32] A variety of scaffolds are available, e.g., commercial polyamidoamine PAMAM, which can be used to synthesize multivalent ligands with carbohydrate density increasing with the generation.…”