A new generation of glycomimetics targeting the N-terminal domain of BC2L-C bacterial lectin: design and synthesis

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]. The N-terminal fucose-binding domain of this protein (BC2L-C-nt) represents an interesting target to design new antimicrobials acting by preventing lectin-mediated bacterial adhesion to host cells. We recently reported the design, synthesis and biophysical evaluation of a first generation of glycomimetics targeting BC2L-C-nt [3]. These compounds contain a fucose core connected to fragments able to engage a secondary site of the lectin, in the vicinity of the fucose binding site. BC2L-C-nt ligands with an order of magnitude gain over the parent monosaccharide resulted from the study. With the aim of obtaining ligands with an improved affinity to the target lectin, a new generation of glycomimetic ligands was designed to covalently target two amino acids (Cys72 and Lys108) located near the fucose binding region of BC2L-C-nt (Figure 1A). The novel compounds (Figure 1B) were investigated in silico through non-covalent and covalent docking protocols to evaluate their interaction with BC2L-C-nt. The most promising ligands were selected for synthesis, and for each compound an appropriate synthetic pathway was developed. Further computational studies and synthesis of the novel fucose-derivatives are in progress.