Design, synthesis and activity evaluation of mannose-based DC-SIGN antagonists

Abstract

In this article, we describe the design, synthesis and activity evaluation of glycomimetic DC-SIGN antagonists, that use a mannose residue to anchor to the protein carbohydrate recognition domain (CRD). The molecules were designed from the structure of the known pseudo-mannobioside antagonist 1, by including additional hydrophobic groups, which were expected to engage lipophilic areas of DC-SIGN CRD. The results demonstrate that the synthesized compounds potently inhibit DC-SIGN-mediated adhesion to mannan coated plates. Additionally, in silico docking studies were performed to rationalize the results and to suggest further optimization.

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2011–2012

“…Anti-inflammatory effects (Chung et al, 2012a) Mannosides with hydrophobic substituents TOF Synthesis as DC-SIGN antagonists (Obermajer et al, 2011) 15 N, 13 C 2 8-sialic acid oligomers TOF Evidence for helical structure in a tetramer of 2 8 sialic acid (Battistel et al, 2012) Oligo( -D-glycosyl phosphate) derivatives TOF Use of a phosphoramidite method via boranophosphate intermediates (Fujita et al, 2011b) Orthogonally protected disaccharide MALDI For synthesis of 6-sulfated derivatives with terminal ethylamine (Liu et al, 2012g) Pustulooligosaccharides ( (Yang et al, 2011f) Tri-, penta-, and heptasaccharides, with orthogonally N-protected amino residues TOF Synthesis of four bifunctionalized orthogonally N-protected oligosaccharides derived from lactose and mannose, intended as cross-linking derivatives (Fyrner et al, 2012a) Poly-N-acetyllactosamineextended TOF (DHB) For recognition studies by human and avian influenza A virus hemagglutinins …”

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

“…Notable quality of the adjacent monosaccharide units is that they do not form the same interactions like the "core monosaccharide", but instead form a network of H-bonds, possibly through water molecules. For example, Man4 tetrasaccharide makes contact with DC-SIGN through at least two water molecules, while one stabilizes its binding conformation [18,64]. Alternatively, both "core" and adjacent monosaccharides make surface complementarity and hydrophobic interactions.…”

“…Furthermore, the cyclohexane saccharide mimic lacks glycosidic bond and is thus metabolically stable. Starting from compound 2 or its azido derivative, the group of Bernardi (Obermajer et al) continued to pursue the idea of increasing the binding affinity by identifying two binding areas around Phe313 in the DC-SIGN binding site that were only partially occupied by cocrystallized tetramannoside Man4 [64]. These hydrophobic areas were targeted by attaching different hydrophobic moieties to deprotected carboxylates of pseudo-1,2-mannobioside 2 ( Figure 10).…”

“…Figure 10. Increasing potency of DC-SIGN antagonists by attaching hydrophobic moieties to deprotected carboxylates of 2 to afford 6 and its derivatives [64].…”

Carbohydrate Mimics and Lectins: A Source of New Drugs and Therapeutic Opportunities

“…A structural modification leading to improve affinity of Man-based ligands was recently reported. 49 Examination of the crystal structure of DC-SIGN CRD in complex with tetramannoside Man 4 (PDB code: 1SL4) 51 suggests he presence of a hydrophobic area in the vicinity of the mannose-binding Ca-site of the lectin. Replacing the methyl ester groups on the cyclohexane scaffolds of 1 with secondary amides (Figure 3) led to a series of compounds the bis-amides of 1 (Figure 3) that displayed low M activity in the inhibition of dendritic cells to a mannan coated plate.…”