Titel
Targeting undruggable carbohydrate recognition sites through focused fragment library design
Autor*in
Elena Shanina
Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems
Sakonwan Kuhaudomlarp
University Grenoble Alpes, CNRS, CERMAV
Eike Siebs
Chemical Biology of Carbohydrates (CBCH), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research
... show all
Abstract
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 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.
Stichwort
Chemical librariesScreening
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Communications Chemistry
Band
5
ISSN
2399-3669
Erscheinungsdatum
2022
Publication
Springer Science and Business Media LLC
Erscheinungsdatum
2022
Zugänglichkeit
Rechte
Rechteangabe
© The Author(s) 2022
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