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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.

Author information

1
Abteilung für Biomolekulare Systeme, Max-Planck-Institut für Kolloid- und Grenzflächenforschung, Am Mühlenberg 1, 14476, Potsdam, Germany.
2
Fachbereich für Biologie, Chemie und Pharmazie, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, 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 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.

KEYWORDS:

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

PMID:
28523851
DOI:
10.1002/anie.201701943
[Indexed for MEDLINE]

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