Structural simplification of ps-diMan based glycomimetics as DC-SIGN antagonists

DC-SIGN - Dendritic Cell-Specific ICAM-3-Grabbing Non-integrin – is a tetrameric transmembrane C-type lectin expressed at the surface of dendritic cells which plays a key role in the recognition of several pathogens and viruses, including Dengue and HIV. Over the past decade, several glycomimetic ligands have been designed as potential antagonists of DC-SIGN mediated viral infections by using as template the pseudo-dimannoside (ps-diMan) scaffold, composed of a mannose ring connected to a conformationally locked cyclohexane diol. Enhanced activity and selectivity were achieved through chemical modification of the 2-position of mannose to include a methyleneamminotriazole group, which exploits a recently identified ammonium ion binding site in the DC-SIGN binding region. This design afforded ligand 1, which showed excellent affinity (50 uM) and selectivity (over Langerin) for DC-SIGN. To further simplify the structure of the antagonists, we explored the possibility of capitalizing on the ammonium-binding motif and removing the cyclohexane moiety. This would vastly accelerate ligand synthesis, possibly with negligible effects on biological activity. A small library of 2-triazole substituted mannosides was synthesized and tested by Surface Plasmon Resonance (SPR) in binding inhibition experiments against DC-SIGN and DC-SIGNR. The results will be discussed.