Shanina E.Kuhaudomlarp S.Siebs E.Fuchsberger F.F.Denis M.da Silva Figueiredo Celestino Gomes P.Clausen M.H.Seeberger P.H.Rognan D.Titz A.Imberty A.Rademacher C.Mahidol University2023-06-182023-06-182022-12-01Communications Chemistry Vol.5 No.1 (2022)https://repository.li.mahidol.ac.th/handle/20.500.14594/83544Carbohydrate-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 DC-SIGN-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.Biochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/s42004-022-00679-32-s2.0-8513038642223993669