Enhancing lectin recognition via precise fluorination: Man₅ glycomimetics for targeting DC-SIGN

Area of Science:

• Carbohydrate Chemistry
• Glycobiology
• Medicinal Chemistry

Background:

• High-mannose N-glycans are crucial DC-SIGN ligands but difficult to synthesize.
• Developing effective glycomimetics is key for understanding and targeting lectin recognition.

Purpose of the Study:

• To create accessible glycomimetics that enhance DC-SIGN recognition through precise fluorination.
• To investigate the impact of selective fluorination on the binding affinity of Man5-based glycomimetics to DC-SIGN.

Main Methods:

• Synthesis of four fluorinated Man5 derivatives with selective C-2 and/or C-6 substitution.
• Biophysical evaluation including affinity measurements and binding epitope mapping (NMR).
• Molecular dynamics (MD) simulations and Isothermal Titration Calorimetry (ITC) to analyze binding interactions and thermodynamics.

Main Results:

• Fluorination at C-6 significantly increased binding affinity, while C-2 substitution decreased it.
• The (6F,6F)-Man5 derivative demonstrated superior inhibitory potency against DC-SIGN, outperforming natural Man5 and Man9.
• Fluorination enhanced binding through favorable enthalpic contributions, including polar interactions and desolvation.

Conclusions:

• Selective fluorination is a powerful strategy for enhancing lectin ligand affinity.
• Fluorinated Man5 glycomimetics show promise as potent agents for targeting DC-SIGN.
• This approach can lead to novel therapeutics for DC-SIGN mediated diseases and viral infections, such as SARS-CoV-2.