Achieving High Affinity for a Bacterial Lectin with Reversible Covalent Ligands

Area of Science:

• Microbiology
• Biochemistry
• Medicinal Chemistry

Background:

• Developing high-affinity monovalent ligands for lectins is difficult due to weak binding.
• Bacterial lectins are potential targets for antiadhesion therapy against infections.
• BC2L-C lectin from *Burkholderia cenocepacia* recognizes host cell oligosaccharides.

Purpose of the Study:

• To design and synthesize rational covalent ligands targeting the BC2L-C lectin N-terminal domain.
• To investigate the potential of these ligands for antiadhesion therapy against *Burkholderia cenocepacia*.

Main Methods:

• Computational design of reversible covalent competitive ligands with a fucoside anchor and salicylaldehyde warhead.
• Synthesis and testing of candidate ligands using competition experiments.
• Mass analysis to confirm covalent interactions.

Main Results:

• The most effective ligand enhanced methyl-fucoside IC50 by two orders of magnitude.
• Ligand affinity matched that of the native H-type 1 trisaccharide.
• Control experiments validated the importance of both the fucose anchor and salicylaldehyde moiety.

Conclusions:

• Rationally designed covalent ligands can achieve high affinity for bacterial lectins.
• These ligands demonstrate potential for antiadhesion therapy against *Burkholderia cenocepacia* infections.
• Covalent targeting of Lys108 in BC2L-C lectin is a viable strategy.