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Publication Abstract from PubMed

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 Ca(2+)-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 Ca(2+)-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 Ca(2+)-dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns.

Targeting undruggable carbohydrate recognition sites through focused fragment library design.,Shanina E, Kuhaudomlarp S, Siebs E, Fuchsberger FF, Denis M, da Silva Figueiredo Celestino Gomes P, Clausen MH, Seeberger PH, Rognan D, Titz A, Imberty A, Rademacher C Commun Chem. 2022 May 20;5(1):64. doi: 10.1038/s42004-022-00679-3. PMID:36697615^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.