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

Angewandte Chemie - International Edition

4 years ago

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

Christoph Rademacher, Dieter E. Kaufmann, Hannes Baukmann, Jonas Hanske, Elena Shanina, Jonas Aretz, Robert Wawrzinek, Viktor A. Zapol'skii, Peter H. Seeberger

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. Multiple binding sites: DC-SIGN, which has been known for 15 years for its role in the HIV transinfection of T cells, is one of the most attractive targets among glycan-binding proteins. Nevertheless, drug-like effectors are sparse but its undruggable primary site might be bypassed by targeting druggable secondary sites.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201701943