Precision glycodendrimers for DC‐SIGN targeting

International audienceMultivalent ligands of the C‐type lectin receptor DC‐SIGN have emerged as effective antiadhesive agents against various pathogens. Some years ago, we described a hexavalent DC‐SIGN ligand, Polyman‐26, designed to bridge two of the four binding sites displayed by the receptor. In this work, we present our efforts to accomplish simultaneous coordination of all four carbohydrate binding sites of DC‐SIGN through the synthesis of cross‐shaped glycodendrimers. The tailored rigid scaffold allowed multivalent presentation of glycomimetics in a spatially defined fashion, while providing good water solubility to the constructs. Evaluation of the biological activity by SPR assays revealed strong binding avidity towards DC‐SIGN and increased selectivity over langerin. Inhibition of DC‐SIGN binding to SARS‐CoV‐2 spike protein and of DC‐SIGN mediated Ebola virus trans‐infection testifies for the glycodendrimers potential application in infection diseases. The tetravalent platform described here is easily accessible and can be used in modular fashion with different ligands, thus lending itself to multiple applications.Multivalent antagonists able to reach the four carbohydrate recognition domains (CRD) of DC‐SIGN have been prepared. The extended rigid core of these glycodendrimers allows multivalent presentation of glycomimetic molecules in a spatially defined fashion, providing high affinity towards DC‐SIGN and selectivity over other C‐type lectins featuring distinct CRD arrangements. The constructs successfully inhibit DC‐SIGN binding to SARS‐CoV‐2 spike protein and DC‐SIGN mediated trans‐infection by Ebola virus