Multivalency is a key principle in Nature for achieving strong reversible interactions between cells or between cells and pathogens. In contrast to weak monovalent binding, multivalent interactions can dramatically enhance binding on a molecular level. DC-SIGN (dendritic cell-specific ICAM-3 grabbing nonintegrin) is a tetramericC-type lectin presenting four copies of a carbohydrate recognition domain at theC-terminus. This calcium dependent lectin specifically recognizes highly-mannosylated or fucosylated structures present at the surface of several pathogens and it is considered as a new target for the design of anti-infective agents. The clustered organization of DC-SIGN as well as high glycosylation of their natural ligands create the conditions for more specific multivalent interactions.
We synthesized monovalent C-glycosides 1 and 2 by a multistep synthesis starting from methyl α,D-mannopyranoside and L-fucose, resp. According to SPR assay, glycoside 1 had the same affinity for DC-SIGN as D-mannose, while glycoside 2 had four times higher activity than L-fucose. Pseudo-C-disaccharides 3 and 4 characterised by two fucose/mannose units connected by a flexible linker were relatively efficient DC-SIGN antagonists: 3, IC500.31 mM and 4, IC501.52 mM.
Using click chemistry both glycosides 1 and 2 were incorporated into six dendrimeric structures having the binding activity in the range from 18 to 163 µM. In this case, the affinity of multivalent presentations were more then 1,000times higher than this of parent glycosides 1 and 2.
In conclusion, C-glycosides are at least as strong ligands as parent saccharides, so the more conformationally flexible C-glycosidic bond does not destroy the affinity. Simple C-glycosides as well as C-disaccharides based on the L-fucose scaffold were more efficient ligands for DC-SIGN than these derived from d-mannose. Finally, we verified high efficiency of polyvalent presentations when designing antagonists of C-type lectins.
The financial support of the EU RTN CARMUSYS (PITN-GA-2008-213592) is acknowledged.
