Drug-like Inhibitors of DC-SIGN Based on a Quinolone Scaffold

Zhang Hengxi, Ondřej Daněk, Dmytro Makarov, Stanislav Rádl, Dongyoon Kim, Jiří Ledvinka, Kristýna Vychodilová, Jan Hlaváč, Jonathan Lefebre, Maxime Denis, Christoph Johannes Heinrich Rademacher

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a pattern recognition receptor expressed on immune cells and involved in the recognition of carbohydrate signatures present on various pathogens, including HIV, Ebola, and SARS-CoV-2. Therefore, developing inhibitors blocking the carbohydrate-binding site of DC-SIGN could generate a valuable tool to investigate the role of this receptor in several infectious diseases. Herein, we performed a fragment-based ligand design using 4-quinolone as a scaffold. We synthesized a library of 61 compounds, performed a screening against DC-SIGN using an STD reporter assay, and validated these data using protein-based 1H–15N HSQC NMR. Based on the structure–activity relationship data, we demonstrate that ethoxycarbonyl or dimethylaminocarbonyl in position 2 or 3 is favorable for the DC-SIGN binding activity, especially in combination with fluorine, ethoxycarbonyl, or dimethylaminocarbonyl in position 7 or 8. Furthermore, we demonstrate that these quinolones can allosterically modulate the carbohydrate binding site, which offers an alternative approach toward this challenging protein target.
OriginalspracheEnglisch
Seiten (von - bis)935-942
Seitenumfang8
FachzeitschriftACS Medicinal Chemistry Letters
Jahrgang13
Ausgabenummer6
DOIs
PublikationsstatusVeröffentlicht - 9 Juni 2022

ÖFOS 2012

  • 301207 Pharmazeutische Chemie

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