期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 13, 期 6, 页码 935-942出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00067
关键词
Fragment-based ligand design; Lectin; DC-SIGN; NMR; Structure-activity relationship; 4-Quinolone
资金
- Institute of Organic Chemistry and Biochemistry, Prague
- China Scholarship Council
- Czech Science Foundation [18-26557Y]
- Max Planck Society
- University of Chemistry and Technology, Prague
DC-SIGN is a pattern recognition receptor expressed on immune cells that recognizes carbohydrate signatures on pathogens. This study focuses on developing inhibitors that can block the carbohydrate-binding site of DC-SIGN. By screening a library of compounds and validating the data, the researchers identified certain compounds with favorable binding activity and demonstrated their ability to modulate the carbohydrate binding site.
DC-SIGN (dendritic cell-specific intercellular adhe-sion 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 H-1-N-15 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.
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