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

Fiche publication

Date publication

mai 2019

Journal

European journal of medicinal chemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr MUELLER Christopher , Dr FLACHER Vincent

Tous les auteurs :
Schaeffer E, Sánchez-Fernández EM, Gonçalves-Pereira R, Flacher V, Lamon D, Duval M, Fauny JD, García Fernández JM, Mueller CG, Ortiz Mellet C

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30870792

Résumé

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.