Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition and
thus, emerged as viable therapeutic targets. However, their hydrophilic nature poses major
limitations to the conventional development of drug-like inhibitors. To address this shortcoming, four fragment libraries were screened to identify metal-binding pharmacophores
(MBPs) as novel scaffolds for inhibition of Ca2+-dependent carbohydrate-protein interactions. Here, we show the effect of MBPs on the clinically relevant lectins DC-SIGN, Langerin,
LecA and LecB. Detailed structural and biochemical investigations revealed the specificity of
MBPs for different Ca2+-dependent lectins. Exploring the structure-activity relationships of
several fragments uncovered the functional groups in the MBPs suitable for modification to
further improve lectin binding and selectivity. Selected inhibitors bound efficiently to DCSIGN-expressing cells. Altogether, the discovery of MBPs as a promising class of Ca2+-
dependent lectin inhibitors creates a foundation for fragment-based ligand design for future
drug discovery campaigns