Design, synthesis and biophysical evaluation of covalent ligands targeting a lysine residue in BC2L-C bacterial lectin

The opportunistic Gram-negative pathogen Burkholderia cenocepacia is a globally spread, multidrug-resistant bacterium causing deadly lung infections in immunocompromised or cystic fibrosis patients. It uses lectins, carbohydrate-binding proteins, as virulence factors to adhere to host tissues by recognizing glycoconjugates on host cell surfaces. Among these, BC2L-C is a key player in adhesion, with its N-terminal fucose-binding domain (BC2L-C-Nt) being a promising target for designing new antimicrobials to prevent lectin-mediated bacterial adhesion [1]. A first generation of glycomimetics targeting BC2L-C-Nt has been recently reported. These compounds contain a fucose residue connected to fragments capable of engaging a secondary site in the lectin, near the fucose-binding region. Some of these compounds demonstrated up to a 10-fold increase in affinity compared to the parent monosaccharide [2]. With the aim of improving the affinity with the target lectin, a new generation of ligands was designed to interact covalently with a lysine residue (Lys108) close to the fucose binding region (Figure 1A). The designed compounds feature a fucose core linked to a spacer with an electrophilic group to react with Lys108. Synthesized and evaluated using various biophysical techniques, these ligands showed a two-order magnitude increase in lectin binding compared to the non-covalent parent monosaccharide, proving the effectiveness of the covalent strategy in targeting bacterial lectins