Synthesis of Novel DC‐SIGN Ligands with an α‐Fucosylamide Anchor

Abstract

The dendritic cell-specific intercellular adhesion molecule (ICAM) 3-grabbing nonintegrin (DC-SIGN) is a C-type lectin that appears to perform several different functions. Besides mediating adhesion between dendritic cells and T lymphocytes, DC-SIGN recognizes several pathogens some of which, including HIV, appear to exploit it to invade host organisms. The intriguing diversity of the roles attributed to DC-SIGN and their therapeutic implications have stimulated the search for new ligands that could be used as biological probes and possibly as lead compounds for drug development. The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. Using the known 3D structure of the Lewis-x trisaccharide, we have identified some monovalent alpha-fucosylamides that bind to DC-SIGN with inhibitory constants 0.4-0.5 mM, as determined by SPR, and have characterized their interaction with the protein by STD NMR spectroscopy. This work establishes for the first time alpha-fucosylamides as functional mimics of chemically and enzymatically unstable alpha-fucosides and describes interesting candidates for the preparation of multivalent systems able to block the receptor DC-SIGN with high affinity and with potential biomedical applications.

DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

“…Furthermore, the mannose-and fucose-based ligands have overlapping, but different binding modes, which might offer a rational explanation for the different biological effects of mannose-and fucose-based ligands [49]. Consequently, the two observed binding modes offer a solid basis upon which DC-SIGN antagonists with either fucose or mannose anchors can be designed [50].…”

“…The most extensive work regarding the choice of the monosaccharide unit comes from the work of Bernardi and Rojo's groups from CARMUSYS [41,50,57]. In particular, they have shown that L-fucose can be incorporated in glycomimetic surrogates of Lewis-X trisaccharide to obtain even better affinity than the native trisaccharide.…”

“…In particular, they have shown that L-fucose can be incorporated in glycomimetic surrogates of Lewis-X trisaccharide to obtain even better affinity than the native trisaccharide. The full Lewis-X mimetic 1 was shown to inhibit DC-SIGN binding of mannosylated BSA in the upper micromolar range (IC50=350 μM), but the second generation of analogous compounds failed to give any significant improvement over 1 ( Figure 6) [50,58]. STD-NMR studies of 1 with DC-SIGN ECD have shown that only fucose residue makes strong contact with the DC-SIGN CRD.…”

“…However, unwanted inhibition of glycosidases may as well provoke side effects of potential drugs, so careful choice of glycosidic bond surrogates has to be made if only its stability is the ultimate goal. The -glycosidic bond found in both Lfucose and D-mannose containing oligosaccharides that bind to DC-SIGN was successfully replaced by Timpano et al by a stable -fucosylamide structure (compound 1, Figure 6) and shown not to affect the binding affinity in a detrimental sense [50]. The derivatives of reduced shikimic acid (compound 4, Figure 6) have 2 features that influence glycosidic bond stability: first, they have a thioglycosidic bond, which is proven to be metabolically more stable towards glycosidases [62], and second, they are a constitute of reduced shikimic acid which is a carbasugar.…”

“…This implies that altering hydrophilic character of adjacent monosaccharide units to more hydrophobic surrogates should increase free binding energy by increasing hydrophobic interactions. With this in mind, Timpano et al have used the (1S,2R)-2-aminocyclohexanecarboxylic acid as a scaffold/linker to attach Dgalactose mimetic into the structure of compound 1 and its derivatives ( Figure 8) [50]. The molecule was carefully chosen to mimic Lewis-X structure while minimizing the hydrophilic ballast of the Lewis-X, and galactose mimetic was incorporated based on the observation, that galactose residue makes contact with the DC-SIGN CRD surface and is thus important in binding [18].…”