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Drug-like Inhibitors of DC-SIGN Based on a Quinolone Scaffold
Hengxi Zhang1,2,3,4, Ondřej Daněk5, Dmytro Makarov5
1Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
ACS Medicinal Chemistry Letters
|June 16, 2022
Summary
Researchers developed novel 4-quinolone compounds that inhibit DC-SIGN, a key receptor for pathogens like HIV and SARS-CoV-2. These inhibitors offer a new strategy for studying infectious diseases by targeting the DC-SIGN carbohydrate-binding site.
Area of Science:
- Immunology
- Medicinal Chemistry
- Structural Biology
Background:
- Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a pattern recognition receptor on immune cells.
- DC-SIGN recognizes carbohydrate structures on pathogens such as HIV, Ebola, and SARS-CoV-2.
- Inhibitors of DC-SIGN's carbohydrate-binding site are valuable tools for studying infectious diseases.
Purpose of the Study:
- To design and synthesize novel inhibitors targeting the DC-SIGN carbohydrate-binding site.
- To explore the structure-activity relationships of 4-quinolone derivatives against DC-SIGN.
- To investigate the potential of these compounds as allosteric modulators of DC-SIGN.
Main Methods:
- Fragment-based ligand design utilizing a 4-quinolone scaffold.
- Synthesis of a library of 61 compounds.
- Screening against DC-SIGN using a saturation transfer difference (STD) reporter assay.
- Validation of binding data using protein-based 1H-15N HSQC NMR.
Main Results:
- Identified favorable substitutions (ethoxycarbonyl or dimethylaminocarbonyl at positions 2 or 3) for DC-SIGN binding.
- Determined that fluorine, ethoxycarbonyl, or dimethylaminocarbonyl at positions 7 or 8 enhance binding activity.
- Demonstrated allosteric modulation of the DC-SIGN carbohydrate-binding site by the synthesized quinolones.
Conclusions:
- Novel 4-quinolone derivatives effectively bind to DC-SIGN.
- Specific structural features enhance the inhibitory activity against DC-SIGN.
- These compounds represent a promising alternative approach for targeting DC-SIGN and investigating its role in infectious diseases.
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