DC-SIGN is a type II C-type lectin expressed exclusively on dendritic cells (DCs) that allows DC migration and docking of pathogens for further processing and ultimate presentation to T cells. DC-SIGN specifically recognizes complex mannose- and fucose-based glycans on the microorganism and endogenous cell surface. Several pathogens exploit DC-SIGN to escape the immune system surveillance: by binding to DC-SIGN they are internalized in DCs, but escape lytic processing in DCs’ endosomes until delivered to the cells to be infected. Prevention of pathogen adhesion to DC-SIGN by its inhibitors is thus a plausible mechanism towards novel antiviral or antibacterial agents.<br/>In order to design potent DC-SIGN antagonists one has to tackle a non-druggable DC-SIGN binding site with low structural complementarity to native ligands; the evidence for that is offered by its extremely low binding affinities for monosaccharides (in milimolar range) and by mere size of the DC-SIGN binding site. Further drawback comes from the nature of DC-SIGN: it exists in a tetrameric form with 4 carbohydrate-binding domains, which binds pathogen glycans by virtue of multiple interactions.<br/>Our group has demonstrated that small molecule DC-SIGN ligands can be designed and reach up to 3 orders of magnitude more potent affinities for DC-SIGN. Although still in micromolar range, these monomeric units may be attached to polymeric cores with vastly improved potency (Figure). In particular, tetrameric presentation of a trisaccharide glycomimetic DC-SIGN inhibitor was potent enough to allow successful inhibition of HIV-1 transfection to CD4+ T lymphocytes. Small-molecule DC-SIGN ligands were found to be internalized to DC-SIGN early endosomes and may just compete with pathogens as this is exactly the “hot spot” where pathogens are believed to survive DCs degradation pathways. These results and others’ results will be discussed to corroborate the validity of the “polyvalent” approach towards potent DC-SIGN inhibitors.

Highs and lows of DC-SIGN inhibitors design

254th National Meeting (2017)

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