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sp 2 -Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo

Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp -iminosugar glycolipids (sp -IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp -IGLs for th...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2019-03, Vol.169, p.111
Main Authors: Schaeffer, Evelyne, Sánchez-Fernández, Elena M, Gonçalves-Pereira, Rita, Flacher, Vincent, Lamon, Delphine, Duval, Monique, Fauny, Jean-Daniel, García Fernández, José M, Mueller, Christopher G, Ortiz Mellet, Carmen
Format: Article
Language:English
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Summary:Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp -iminosugar glycolipids (sp -IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp -IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1R)-1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO -ONJ), able to inhibit LPS-induced TNFα production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp -IGLs: unlike MGCs, DSO -ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO -ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp -IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling.
ISSN:1768-3254