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

Angewandte Chemie
Jonas AretzChristoph Rademacher

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.

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Citations

Jun 8, 2018·Chemical Communications : Chem Comm·Martin PawliczekKeiji Maruoka
Jul 31, 2019·Medicinal Research Reviews·Alice TamburriniAnna Bernardi
May 20, 2020·Chembiochem : a European Journal of Chemical Biology·Pablo ValverdeJesús Jiménez-Barbero
Dec 10, 2019·MedChemComm·Pablo ValverdeAna Gimeno
Dec 19, 2020·Expert Opinion on Drug Discovery·Vishnu C DamalankaJames W Janetka
Aug 31, 2019·Current Opinion in Chemical Biology·Joscha MeiersAlexander Titz
Dec 16, 2019·Current Opinion in Structural Biology·Bettina G Keller, Christoph Rademacher
Dec 15, 2020·Angewandte Chemie·Sakonwan KuhaudomlarpAlexander Titz
Aug 29, 2019·ACS Omega·Maurice MichelThomas Helleday
Nov 28, 2018·ACS Chemical Biology·Jessica SchulzeChristoph Rademacher
Oct 12, 2018·Journal of the American Chemical Society·Jonas AretzChristoph Rademacher
Oct 16, 2021·Journal of the American Chemical Society·Jonathan CramerBeat Ernst
Nov 9, 2021·Journal of the American Chemical Society·Robert WawrzinekChristoph Rademacher
Oct 30, 2021·Angewandte Chemie·Elena ShaninaChristoph Rademacher

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