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

Heavily sulfated clusters of maltose are designed as mimetics of heparan sulfate (HS), exhibiting diverse biological activity properties of HS. Herein, the synthesis of three function-spacer-lipid (FSL) constructs containing mono, di, and tri sulfated maltoses is reported. FSLs are a class of synthetic glycolipids, the key features of which are simplicity of synthesis and capacity to integrate into cell membranes with sustained retention. A copper-catalyzed azide-alkyne cycloaddition click reaction is employed for the conjugation of the sulfated maltose entities with the respective spacer-lipid block because acylation with activated esters failed to provide the desired products. One FSL construct, featuring a single sulfated maltose unit conjugated to the lipid, demonstrated dose-dependent inhibition of complement activation in a cellular system, with maximal efficacy observed at 15 µg mL-1. These findings highlight the potential of FSL-based HS mimetics for modulating immune responses.