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

Hengxi Zhang; Ondřej Daněk; Dmytro Makarov; Stanislav Rádl; Dongyoon Kim; Jiří Ledvinka; Kristýna Vychodilová; Jan Hlaváč; Jonathan Lefèbre; Maxime Denis; Christoph Rademacher; Petra Ménová

doi:10.1021/acsmedchemlett.2c00067

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

ACS Med Chem Lett. 2022 May 10;13(6):935-942. doi: 10.1021/acsmedchemlett.2c00067. eCollection 2022 Jun 9.

Authors

Hengxi Zhang^{1

2

3

4}, Ondřej Daněk⁵, Dmytro Makarov⁵, Stanislav Rádl^{5

6}, Dongyoon Kim^{1

3

4}, Jiří Ledvinka⁵, Kristýna Vychodilová⁷, Jan Hlaváč⁸, Jonathan Lefèbre^{3

4}, Maxime Denis^{3

4}, Christoph Rademacher^{1

2

3

4}, Petra Ménová⁵

Affiliations

¹ Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
² Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
³ Department of Pharmaceutical Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
⁴ Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria.
⁵ University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic.
⁶ Zentiva a.s., U Kabelovny 130, 10237 Prague 10, Czech Republic.
⁷ Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
⁸ Department of Organic Chemistry, Faculty of Science, Palacký University, Tř. 17. Listopadu 12, 77146 Olomouc, Czech Republic.

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.