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.

Department of Biomolecular Systems Max Planck Institute of Colloids and Interfaces Am Mühlenberg 1 14424 Potsdam Germany

Department of Microbiology and Immunobiology Max F Perutz Laboratories University of Vienna Biocenter 5 1030 Vienna Austria

Department of Organic Chemistry Faculty of Science Palacký University Tř 17 Listopadu 12 77146 Olomouc Czech Republic

Department of Pharmaceutical Sciences University of Vienna Althanstraße 14 1090 Vienna Austria

Freie Universität Berlin Takustrasse 3 14195 Berlin Germany

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77900 Olomouc Czech Republic

University of Chemistry and Technology Prague Technická 5 16628 Prague 6 Czech Republic

Zentiva a s U Kabelovny 130 10237 Prague 10 Czech Republic

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Glycomimetics for the inhibition and modulation of lectins