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.
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Abbreviations
- BSA:
-
Bovine serum albumin
- CFSE:
-
Carboxyfluorescein succinimidyl ester
- CRD:
-
Carbohydrate- recognition domain
- DC:
-
Dendritic cell
- DCC:
-
Dicyclohexyl carbodiimide
- DC-SIGN:
-
Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin
- DMA:
-
N,N-Dimethylacetamide
- DMAP:
-
4-Dimethylaminopyridine
- DMSO:
-
Dimethyl sulfoxide
- EDC:
-
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide
- FBS:
-
Fetal bovine serum
- HATU:
-
O-(7-Azabenzotriazole)- N,N,N′,N′ - tetramethyluronium hexafluorophosphate
- LPS:
-
Lipopolysaccharide
- MCPBA:
-
m-Chloroperoxybenzoic acid
- PAMPs:
-
Pathogen-associated molecular patterns
- PBS:
-
Phosphate buffered saline
- PFP:
-
Pentafluorophenyl
- rhGM-CSF:
-
Recombinant human granulocyte-macrophage colony-stimulating factor
- rhIL-4:
-
Recombinant human interleukin-4
- RMSD:
-
Root mean square deviation
- SAR:
-
Structure–activity relationship
- SDS:
-
Sodium dodecyl sulfate
- SPR:
-
Surface-plasmon resonance
- THF:
-
Tetrahydrofuran
- TLC:
-
Thin-layer chromatography
- TLR:
-
Toll-like receptor
- ManLAM:
-
Mannosylated lipoarabinomannan
- TMSOTf:
-
Trimethylsilyl triflate
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Obermajer, N., Sattin, S., Colombo, C. et al. Design, synthesis and activity evaluation of mannose-based DC-SIGN antagonists. Mol Divers 15, 347–360 (2011). https://doi.org/10.1007/s11030-010-9285-y
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DOI: https://doi.org/10.1007/s11030-010-9285-y