Dynamic Combinatorial Chemistry Generates Adaptative Libraries of Glyco-Dyn[n]Arenes That can Be Templated to Produce Anti-Adhesive Glycoconjugates Targeting Pseudomonas aeruginosa

Abstract

Carbohydrate-protein interactions are important in cell-cell communication, signal transduction, cancer, or infection. Chemists have designed glycosylated multivalent systems to mimic these recognition phenomena and produce potent ligands of lectins with therapeutic applications. Dynamic combinatorial chemistry (DCC) provides access to libraries of glycosylated macrocycles equilibrating through reversible covalent bonds. This strategy can be applied to the rapid and efficient identification of multivalent glycoclusters by introducing a protein into the equilibrating library. This strategy allowed the identification of the best ligands for more than one lectin in a single experimental set up by using two simple 1,4-dithiophenol building blocks. Selection of the best binder by each lectin (ConA, LecA, and LecB) was accompanied by the amplification of glyco-dyn[3]arenes and glyco-dyn[4]arenes. These macrocycles could be synthesized, isolated, and displayed nanomolar dissociation constants. Furthermore, while no toxicity could be detected against human cells or bacteria, their anti-adhesive properties against Pseudomonas aeruginosa were confirmed through a virulence assay on human cells. Altogether, extremely simple 1,4-dithiophenol building blocks provided access to a large diversity of glycoconjugates that could be selected by a lectin in a simple experimental set up to identify glycoconjugates with potential anti-infectious applications, thus speeding up the discovery of potential new antibacterial treatments.