DC-SIGN as a Target for Drug Development Based on Carbohydrates

Rational-Differential Design of Highly Specific Glycomimetic Ligands: Targeting DC-SIGN and Excluding Langerin Recognition

“…To date, issues involving biostability and bioavailability, [13][14][15][16] heterogeneous modes of binding with the Ca 2+ binding site, and weak protein-carbohydrate affinity have been successfully addressed for DC-SIGN by several groups. 13,[17][18][19] Our previous work set out to rationally design glycosidase-resistant glycomimetic ligands that bound to DC-SIGN with binding modes similar to the natural ligands. From this approach, we identified two glycomimetics, a pseudo-di and a pseudo-trisaccharide, as lead compounds able to bind efficiently DC-SIGN and even to be effective in anti-HIV trans-infection test (Figure 1B).…”

“…DC-SIGN, one of the most investigated CLRs up to now, is a good example of the cumulative difficulties typically encountered with CLRs. To date, issues involving biostability and bioavailability, − heterogeneous modes of binding with the Ca 2+ binding site, and weak protein–carbohydrate affinity have been successfully addressed for DC-SIGN by several groups. ,− Our previous work set out to rationally design glycosidase-resistant glycomimetic ligands that bound to DC-SIGN with binding modes similar to the natural ligands. From this approach, we identified two glycomimetics, a pseudodi- and a pseudotrisaccharide, as lead compounds able to bind efficiently DC-SIGN and even to be effective in anti-HIV trans -infection test (Figure B). − However, because of the unpredictable multiple binding mode of carbohydrates with CLRs, − we have been able to establish that only the pseudodisaccharide 1 meets the requirement of a unique binding mode within DC-SIGN (Figure C) and allows further rational molecule improvement.…”