Lefèbre, Jonathan and Besch, Maurice and Csorba, Noémi and Garami, Kristóf Noel and Orgován, Zoltán and Schlosser, Gitta and Bermejo, Iris and Ábrányi-Balogh, Péter and Keserű, György Miklós and Rademacher, Christoph (2026) Covalent Activation of the C‐type Lectin DC‐SIGN. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 65 (3). No. e20594. ISSN 1433-7851
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ACIE_2026_Lefebre_CsN_DCSign_Lys.pdf - Published Version Available under License Creative Commons Attribution Non-commercial. Download (2MB) | Preview |
Abstract
Dendritic cell‐specific intercellular adhesion molecule‐3‐grabbing non‐integrin (DC‐SIGN) is a C‐type lectin receptor expressed on antigen‐presenting cells, crucial for pathogen recognition and immune modulation. The shallow and polar carbohydrate binding site of DC‐SIGN presents challenges for ligand design. Here, we explored covalent modification targeting specific lysine residues as a novel strategy to modulate DC‐SIGN function. Screening a lysine‐targeted electrophilic fragment library using orthogonal functional assays identified two potent activators. Structural analyses via NMR spectroscopy, mass spectrometry and computational modeling confirmed structural perturbations of the carbohydrate recognition domain (CRD) and revealed distinct mechanisms of activation. While both activators significantly enhanced DC‐SIGN's affinity for monosaccharide ligands, one compound induced oligomerization via covalent coupling and non‐covalent secondary site interactions, whereas the other selectively modified lysine K373 directly within the primary carbohydrate binding site. These findings demonstrate the potential of lysine‐targeted covalent compounds as a novel therapeutic strategy for modulating DC‐SIGN function and potentially C‐type lectins in general.
| Item Type: | Article |
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| Additional Information: | C.R., J.L. and G.M.K thank the funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska Curie grant agreement no. 956314 ALLODD. M.B. thanks the funding from National Research Fund, Luxembourg, AFR PhD Grant 17929849. This study was supported by the National Laboratory for Drug Research and Development (PharmaLab) project (RRF-2.3.1-21-2022–00015). K.G. was supported by the Doctoral Excellence Fellowship Programme (DCEP-25-1-BME-53) funded by the National Research Development and Innovation Fund of the Ministry of Culture and Innovation and the Budapest University of Technology and Economics. I.A.B. thanks the European Commission for a Marie-Skłodowska Curie Fellowship (No. 895202). P. Á.-B. is supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors would like to thank the NMR facility at the Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, for providing critical support and access to instrumentation for this work. Open access funding provided by Universitat Wien/KEMO. |
| Subjects: | Q Science / természettudomány > QD Chemistry / kémia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 24 Sep 2026 09:07 |
| Last Modified: | 24 Sep 2026 09:07 |
| URI: | https://real.mtak.hu/id/eprint/247452 |
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