Engagement of a Neighboring Lys Residue by a Salicylaldehyde-Modified Glycomimetic Ligand Enables Potent and Selective Binding to DC-SIGN Over L-SIGN

The derivatization of small molecule ligands with salicylaldehyde (SA) tags is being increasingly pursued to form imine adducts with protein lysine residues, aiming at strong and selective inhibition of a wide range of protein targets. In this work, we describe SA-tagged, glycomimetic ligands specific for the human C-type lectin DC-SIGN. Covalent docking studies guided the SA installation at the anomeric position of mannose scaffolds, enabling imine bond formation with a Lys residue in the vicinity of the ligand binding site. Compared to control compounds, the synthesized SA-bearing glycomimetics showed improved binding to DCSIGN and exquisite selectivity for this lectin over the closely-related L-SIGN, where the relevant Lys are replaced by different residues. Mass spectrometry data confirmed the formation of a covalent adduct between the SA-tagged ligand and DC-SIGN, ultimately confirming the potential of SA-tagged glycomimetics as drug candidates against viral infections.