| Affiliation: | 1. 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;2. Abteilung für Biomolekulare Systeme, Max-Planck-Institut für Kolloid- und Grenzflächenforschung, Am Mühlenberg 1, 14476 Potsdam, Germany;3. Institut für Organische Chemie, Technische Universität Clausthal, Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany |
| Abstract: | 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 19F NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and 1H–15N 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. |
