From optimized monovalent ligands to size-controlled dendrimers: An efficient strategy towards high-activity DC-SIGN antagonists

This short review describes our work on the development of dendrimeric antagonists of DC-SIGN, a dendritic cells (DCs) receptor recognizing highly mannosylated structures and primarily involved in the recognition of viruses such as HIV. The structure of pseudo-di-mannoside and pseudo-tri-mannoside compounds was first finely modified to obtain DC-SIGN ligands that were more stable and selective than mannose. Their DC-SIGN affinity differences were amplified once presented on multivalent dendrimer-like scaffolds, including poly-alkyne terminated and phenylene-ethynylene rod-like ones. Libraries of mannosylated dendrimers were synthesized, improving their stability and maximizing their monodispersity. The effect of the dendrimers valency, structure, and size on DC-SIGN affinity and antiviral potency was investigated. Both the valency and the topology of the architectures were revealed as key parameters for activity optimization, together with the intrinsic affinity of the monovalent ligand. The stability, rigidity, and length of the scaffolds were also tuned. The design of geometrically adapted scaffolds afforded one of the most potent inhibitors of DC-SIGN mediated HIV infections to date. This monodispersed, not cytotoxic, and highly active compound was also tested with DCs; its internalization into endolysosomal compartments and its ability to induce the overexpression of signaling molecules makes it a good precursor to produce pathogen-entry inhibitors with immunomodulant properties.