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Angew Chem Int Ed Engl. 2017 Jun 12;56(25):7292-7296. doi: 10.1002/anie.201701943. Epub 2017 May 19.

Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC-SIGN.

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Abteilung für Biomolekulare Systeme, Max-Planck-Institut für Kolloid- und Grenzflächenforschung, Am Mühlenberg 1, 14476, Potsdam, Germany.
Fachbereich für Biologie, Chemie und Pharmazie, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany.
Institut für Organische Chemie, Technische Universität Clausthal, Leibnizstrasse 6, 38678, Clausthal-Zellerfeld, Germany.


DC-SIGN is a cell-surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis. Multiple attempts to develop inhibitors of the underlying carbohydrate-protein interactions have been undertaken in the past fifteen years. Still, drug-like DC-SIGN ligands are sparse, which is most likely due to its hydrophilic, solvent-exposed carbohydrate-binding site. Herein, we report on a parallel fragment screening against DC-SIGN applying SPR and a reporter displacement assay, which complements previous screenings using 19 F NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and 1 H-15 N HSQC NMR spectroscopy revealed that although no fragment bound in the primary carbohydrate site, five secondary sites are available to harbor drug-like molecules. Building on key interactions of the reported fragment hits, these pockets will be targeted in future approaches to accelerate the development of DC-SIGN inhibitors.


NMR spectroscopy; drug discovery; fragment-based drug design; glycan-binding proteins; surface plasmon resonance

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