title: Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like receptor 4 (TLR4) modulators.
abstract: An increasing number of pathologies have been linked to Toll-like receptor 4 (TLR4) activation and signaling, therefore new hit and lead compounds targeting this receptor activation process are urgently needed. We report on the synthesis and biological properties of glycolipids based on glucose and trehalose scaffolds which potently inhibit TLR4 activation and signaling in vitro and in vivo. Structure-activity relationship studies on these compounds indicate that the presence of fatty ester chains in the molecule is a primary prerequisite for biological activity and point to facial amphiphilicity as a preferred architecture for TLR4 antagonism. The cationic glycolipids here presented can be considered as new lead compounds for the development of drugs targeting TLR4 activation and signaling in infectious, inflammatory, and autoimmune diseases. Interestingly, the biological activity of the best drug candidate was retained after adsorption at the surface of colloidal gold nanoparticles, broadening the options for clinical development.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla , E-41012 Sevilla, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Rodriguez Lavado
authors.forename: Stefania E
authors.initials: SE
authors.lastname: Sestito
authors.forename: Roberto
authors.initials: R
authors.lastname: Cighetti
authors.forename: Eva M
authors.initials: EM
authors.lastname: Aguilar Moncayo
authors.forename: Alja
authors.initials: A
authors.lastname: Oblak
authors.forename: Duško
authors.initials: D
authors.lastname: Lainšček
authors.forename: José Luis
authors.initials: JL
authors.lastname: Jiménez Blanco
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García Fernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
authors.forename: Valentina
authors.initials: V
authors.lastname: Calabrese
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000037:antagonists & inhibitors; D005947:Glucose / Q000031:analogs & derivatives*; D006017:Glycolipids / Q000138:chemical synthesis* / Q000494:pharmacology; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D053768:Metal Nanoparticles / Q000737:chemistry; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014199:Trehalose / Q000031:analogs & derivatives*
chemical_list: D004731:Endotoxins; D006017:Glycolipids; D013501:Surface-Active Agents; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C044101:endotoxin, Escherichia coli; D014199:Trehalose; D005947:Glucose