AI Article Synopsis
- Developing high-affinity monovalent ligands for lectins is difficult due to weak binding interactions, prompting research into covalent ligands for BC2L-C lectin, which is linked to severe respiratory infections in immunocompromised patients.
- Antiadhesion therapy is gaining traction as a strategy against infections, particularly targeting bacterial lectins like BC2L-C-Nt, which recognizes specific blood group oligosaccharides in host cells.
- Using computational methods, researchers created effective reversible covalent ligands that enhanced their binding affinity significantly, demonstrating the crucial role of specific ligand components in achieving this improved efficacy.
Article Abstract
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 , 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 IC 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.4c01876 | DOI Listing |
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