Multivalent Glycomimetics with Affinity and Selectivity toward Fucose-Binding Receptors from Emerging Pathogens

Area of Science:

• Carbohydrate chemistry
• Microbiology
• Drug discovery

Background:

• Cystic fibrosis lung infections involve bacterial and fungal pathogens.
• These pathogens use fucose-binding lectins on a ring-shaped scaffold for host tissue recognition.
• These lectins are potential targets for anti-infective compounds.

Purpose of the Study:

• To design and synthesize a novel hexavalent compound presenting fucose residues.
• To evaluate the binding avidity and specificity of the synthetic compound against pathogen lectins.
• To explore the potential of fucomimetics for enhanced specificity.

Main Methods:

• Design of a cyclopeptide-based hexavalent structure presenting six fucose residues.
• Synthesis of the hexavalent compound.
• Assessment of binding avidity with lectins from Aspergillus fumigatus and Burkholderia ambifaria.
• Evaluation of a modified compound with a conformationally constrained fucomimetic.

Main Results:

• The synthetic hexavalent compound demonstrated high-avidity binding to lectins from Aspergillus fumigatus and Burkholderia ambifaria.
• The compound's liable geometry contributed to its effective binding.
• Replacing fucose with a fucomimetic maintained affinity but enhanced specificity, preventing binding to other fucose-specific lectins.

Conclusions:

• A novel synthetic hexavalent compound effectively targets fucose-binding lectins from key cystic fibrosis pathogens.
• The compound shows promise as a basis for developing anti-infective strategies.
• Fucomimetic modification offers a route to fine-tune specificity for therapeutic applications.