Synthesis of Lipid-Conjugated Heparan Sulfate Mimetics and Their Effect on Complement Inhibition

Area of Science:

• Carbohydrate Chemistry
• Immunology
• Glycobiology

Background:

• Heparan sulfate (HS) plays crucial roles in various biological processes.
• Developing synthetic HS mimetics is key to understanding and manipulating HS functions.
• Existing synthetic approaches may lack efficiency or membrane integration capabilities.

Purpose of the Study:

• To synthesize novel function-spacer-lipid (FSL) constructs incorporating sulfated maltose as HS mimetics.
• To evaluate the biological activity of these synthetic glycolipids, particularly their effect on immune responses.
• To establish a reliable synthetic route for generating these HS mimetics.

Main Methods:

• Synthesis of mono-, di-, and tri-sulfated maltose units.
• Conjugation of sulfated maltose to a spacer-lipid moiety using copper-catalyzed azide-alkyne cycloaddition (click chemistry).
• Evaluation of complement activation inhibition in a cellular system.

Main Results:

• Successfully synthesized three FSL constructs with varying degrees of maltose sulfation.
• The click chemistry approach proved effective for conjugation, outperforming acylation methods.
• A mono-sulfated maltose FSL construct demonstrated dose-dependent inhibition of complement activation, with maximal efficacy at 15 µg mL⁻¹.

Conclusions:

• Function-spacer-lipid (FSL) constructs serve as effective synthetic mimetics of heparan sulfate (HS).
• The developed synthetic strategy enables the creation of novel glycolipids with potential therapeutic applications.
• These HS mimetics show promise in modulating immune responses, specifically complement activation.