Developing glycomimetic inhibitors for the N-terminal domain of the bacterial lectin BC2L-C through covalent strategies

Burkholderia cenocepacia is an opportunistic human pathogen responsible for deadly lung infections in immunocompromised individuals, and it is highly resistant to most clinically useful antibiotics (1). This bacterium employs lectins as virulence factors to target host tissues through recognition of and adhesion to the glycoconjugates on the host cells’ surface. Among these lectins, the superlectin BC2L-C has been proposed as a major player in the adhesion process and in the formation of bacterial biofilm (2). In particular, its N-terminal fucose-binding domain (BC2L-C-nt) represents an interesting target for design of new antimicrobials that may prevent lectin-mediated bacterial adhesion to the host cells. Based on fragment- and structure-based design studies, we have synthesized and characterized by ITC and X-ray crystallography a group of glycomimetics targeting BC2L-C-nt and containing a fucose residue connected to fragments able to engage a secondary site in the lectin, near the fucose-binding region (3,4,5). This resulted in the first BC2L-C-nt synthetic ligands showing up to a 10-fold affinity gain over the parent monosaccharide (4,6).With the aim of improving the binding affinity, the next generation of ligands was designed to covalently target specific nucleophilic amino acid residues, (Cys72 and Lys108) near the binding site. These glycomimetics were selected in silico through non-covalent and covalent docking protocols, and the most interesting ones were synthetized and subjected to the first biophysical studies showing promising results