Targeting undruggable carbohydrate recognition sites through focused fragment library design

Carbohydrate-protein interactions are crucial for cell-cell and host-pathogen recognition, making them attractive therapeutic targets. However, their hydrophilic nature hinders conventional drug development. This study screened four fragment libraries to identify metal-binding pharmacophores (MBPs) as novel scaffolds for inhibiting Ca²⁺-dependent carbohydrate-protein interactions in lectins DC-SIGN, Langerin, LecA, and LecB. MBPs exhibited lectin-specific effects, and structure-activity relationship studies identified modifiable functional groups for improved binding and selectivity. Selected inhibitors effectively bound to DC-SIGN-expressing cells, establishing MBPs as promising Ca²⁺-dependent lectin inhibitors for future drug discovery.

Elena Shanina, Sakonwan Kuhaudomlarp, Eike Siebs, Felix F. Fuchsberger, Maxime Denis, Priscila da Silva Figueiredo Celestino Gomes, Mads H. Clausen, Peter H. Seeberger, Didier Rognan, Alexander Titz, Anne Imberty, Christoph Rademacher