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Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Multivalent 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Keywords: Carbohydrates; DC-SIGN; Dendrimers; Glycomimetics; Langerin EN Carbohydrates DC-SIGN Dendrimers Glycomimetics Langerin 1 1 1 08/09/22 20220805 NES 220805 B The Front Cover b shows a blueprint for the design of a multivalent ligand of the C-type lectin receptor DC-SIGN. This molecular architecture achieves strong binding avidity towards DC-SIGN and increased selectivity over the C-type lectin langerin, which is characterized by a distinct spatial arrangement of the carbohydrate recognition domains. Carbohydrates, DC-SIGN, Dendrimers, Glycomimetics, Langerin. [Extracted from the article]