Achieving High Affinity for a Bacterial Lectin with Reversible Covalent Ligands

High-affinity monovalent ligands for lectins are challenging
to
develop due to weak binding interactions. This study investigates
the potential of rationally designed covalent ligands targeting the
N-terminal domain of BC2L-C lectin from Burkholderia
cenocepacia, a pathogen causing severe respiratory
infections in immunocompromised patients. Antiadhesion therapy is
emerging as a complementary approach against such infections, and
bacterial lectins are suitable targets. The fucose-specific BC2L-C-Nt
recognizes blood group oligosaccharides on host cells. Using a computational
approach, we designed reversible covalent competitive ligands that
include a fucoside anchor and a salicylaldehyde warhead targeting
Lys108 near the fucose-binding site. Several candidates were synthesized
and tested using competition experiments. The most effective ligand
improved the IC50 of methyl-fucoside by 2 orders of magnitude,
matching the affinity of the native H-type 1 trisaccharide. Control
experiments confirmed the importance of both fucose anchor and salicylaldehyde
moiety in the ligand’s affinity. Mass analysis confirmed the
covalent interaction with Lys108.