Polyvalent C-glycomimetics based on l-fucose or d-mannose as potent DC-SIGN antagonists

Abstract

The C-type lectin DC-SIGN expressed on immature dendritic cells is a promising target for antiviral drug development. Previously, we have demonstrated that mono- and divalent C-glycosides based on d-manno and l-fuco configurations are promising DC-SIGN ligands. Here, we described the convergent synthesis of C-glycoside dendrimers decorated with 4, 6, 9, and 12 α-l-fucopyranosyl units and with 9 and 12 α-d-mannopyranosyl units. Their affinity against DC-SIGN was assessed by surface plasmon resonance (SPR) assays. For comparison, parent O-glycosidic dendrimers were synthesized and tested, as well. A clear increase of both affinity and multivalency effect was observed for C-glycomimetics of both types (mannose and fucose). However, when dodecavalent C-glycosidic dendrimers were compared, there was no difference in affinity regarding the sugar unit (l-fuco, IC 17 μM; d-manno, IC 12 μM). For the rest of glycodendrimers with l-fucose or d-mannose attached by the O- or C-glycosidic linkage, C-glycosidic dendrimers were significantly more active. These results show that in addition to the expected physiological stability, the biological activity of C-glycoside mimetics is higher in comparison to the corresponding O-glycosides and therefore these glycomimetic multivalent systems represent potentially promising candidates for targeting DC-SIGN.

Development of c-type lectin oriented surfaces for high avidity glycoconjugates: towards mimicking multivalent interactions on the cell surface

“…(2)(3)(4) These findings have placed DC-SIGN as an important therapeutic target and many efforts are being invested to develop DC-SIGN antagonists. (5)(6)(7)(8)(9)(10)(11)(12)(13) DC-SIGN is a tetrameric C-type lectin receptor (CLR) with specificity to D-mannose-and L-fucose-containing oligosaccharides that bind the C-terminal carbohydrate recognition domain (CRD) in a Ca2+-dependent manner. (1,14) Although the intrinsic affinity of a single CRD for a monosaccharide is low (KD in mM range), the global DC-SIGN/multivalent carbohydrates interaction affinity is markedly amplified (KD from µM to pM) through the avidity phenomenon.…”

Strategies for the Development of Glycomimetic Drug Candidates

“…Numerous glycomimetics have incorporated multivalency in order to better mimic the multivalent presentation of native ligands [81,87,88,89,90,91]. Multivalency can improve binding affinities in several ways: (i) chelation; (ii) statistical rebinding effects; or (iii) clustering of soluble binding partners [92,93].…”

Lectin PLL3, a Novel Monomeric Member of the Seven-Bladed β-Propeller Lectin Family

“…The synthesis of the pillar [5]arene-based glycoclusters was based on the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) [37][38][39][40][41][42][43][44][45][46][47][48] of propargyl-functionalized pillar [5]arene-based glycoclusters with two azido-functionalized C-l-fucosides with different linkers. The procedure is described in detail in the Supporting Information section (File S1).…”

“…In brief, the conjugation of N-(5-azido-3-oxa-pentyl)-2-(2,3,4-tri-O-acetyl-α-l-fucopyranosyl)ethanamide (2a) or 2-(2,3,4-tri-O-acetyl-α-l-fucopyranosyl)ethylazide (2b) [39] with (propargyl) 10 pillar [5]arene-based glycoclusters (1) [46] provided the acetylated glycoclusters 3a and 3b, respectively (Figure 8). The compounds were synthesized in 70-85% yield as a 1:1 mixture of diastereomers.…”