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 DC‐SIGN 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.
Pollastri et al. (Tue,) studied this question.