Achieving High\nAffinity for a Bacterial Lectin with\nReversible Covalent Ligands

High-affinity monovalent ligands for lectins are challenging\nto\ndevelop due to weak binding interactions. This study investigates\nthe potential of rationally designed covalent ligands targeting the\nN-terminal domain of BC2L-C lectin from Burkholderia\ncenocepacia, a pathogen causing severe respiratory\ninfections in immunocompromised patients. Antiadhesion therapy is\nemerging as a complementary approach against such infections, and\nbacterial lectins are suitable targets. The fucose-specific BC2L-C-Nt\nrecognizes blood group oligosaccharides on host cells. Using a computational\napproach, we designed reversible covalent competitive ligands that\ninclude a fucoside anchor and a salicylaldehyde warhead targeting\nLys108 near the fucose-binding site. Several candidates were synthesized\nand tested using competition experiments. The most effective ligand\nimproved the IC<sub>50</sub> of methyl-fucoside by 2 orders of magnitude,\nmatching the affinity of the native H-type 1 trisaccharide. Control\nexperiments confirmed the importance of both fucose anchor and salicylaldehyde\nmoiety in the ligand’s affinity. Mass analysis confirmed the\ncovalent interaction with Lys108.