Design and synthesis of a new generation of glycomimetics targeting B. cenocepacia's lectin BC2L-C

Burkholderia cenocepacia is an opportunistic human pathogen causing severe lung infections in immunocompromised individuals as cystic fibrosis patients, and it is highly resistant to different classes of antibiotics.1 This bacterium produces different virulence factors, including the super lectin BC2L-C, involved in adhesion and biofilm formation.2 The N-terminal fucose-binding domain of this protein (BC2L-C-nt) represents an interesting target for design of new antimicrobials acting by preventing lectin-mediated bacterial adhesion to the host cells. The design of a first generation of glycomimetics targeting BC2L-C-nt was recently reported.3 They contain a fucose residue connected to fragments able to engage a secondary site in the lectin, near the fucose-binding region. Figure 1. Fucose-binding site in BC2L-C-nt (A) and structure of new covalent ligands (B). Analyzing the fucose binding site, two amino acids (Cys72 and Lys108, Figure 1A) were identified as potential target residues to develop novel covalent glycomimetic ligands (Figure 1B). The compounds were designed in silico and investigated through covalent docking protocols to evaluate the interaction with BC2L-C-nt, and the most promising ones were selected to be synthesized. Further computational studies and synthesis of the novel fucose-derivatives are in progress.