Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 25, Pages 7292-7296Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201701943
Keywords
drug discovery; fragment-based drug design; glycan-binding proteins; NMR spectroscopy; surface plasmon resonance
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Funding
- Max Planck Society
- German Research Foundation (DFG) [RA1944/2-1]
- Boehringer Ingelheim Stiftung
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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 F-19 NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and H-1-N-15 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.
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