Journal
COMMUNICATIONS CHEMISTRY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42004-022-00679-3
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Funding
- German Research Foundation (DFG) [Ti756/5-1, RA1944/7-1]
- German Research Foundation
- French National Research Agency [ANR-17-CE11-0048]
- Max Planck Society
- Olaf Niemeyer
- Glyco@Alps [ANR-15-IDEX-02]
- Labex Arcane/CBH-EUR-GS [ANR-17-EURE-0003]
- Ministry of Higher Education and Science [5072-00019B]
- Technical University of Denmark
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Carbohydrate-protein interactions are crucial for cell-cell and host-pathogen recognition. This study identifies metal-binding pharmacophores as novel scaffolds for inhibiting Ca2+-dependent carbohydrate-protein interactions, addressing the challenge posed by the hydrophilic nature of these interactions.
Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition, but their hydrophilic nature makes the development of drug-like inhibitors a challenge. Here, screening of fragment libraries identifies metal-binding pharmacophores as novel scaffolds for the inhibition of Ca2+-dependent carbohydrate-protein interactions. 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.
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