1. Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like receptor 4 (TLR4) modulators
- Author
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Stefania E. Sestito, Francesco Peri, Duško Lainšček, Roman Jerala, Carmen Ortiz Mellet, Roberto Cighetti, José M. García Fernández, Eva M. Aguilar Moncayo, Julio Rodriguez Lavado, José L. Jiménez Blanco, Valentina Calabrese, Alja Oblak, Rodriguez Lavado, J, Sestito, S, Cighetti, R, Aguilar Moncayo, E, Oblak, A, Lainšček, D, Jiménez Blanco, J, García Fernández, J, Ortiz Mellet, C, Jerala, R, Calabrese, V, Peri, F, and Universidad de Sevilla. Departamento de Química Orgánica
- Subjects
Receptor Activation Process ,LPS ,Macrophage ,Metal Nanoparticles ,Medicinal chemistry ,Drug development ,Glycolipid ,Surface-Active Agent ,chemistry.chemical_compound ,Metal Nanoparticle ,Structure-Activity Relationship ,Surface-Active Agents ,Endotoxin ,HEK293 Cell ,In vivo ,Drug Discovery ,Gold nanoparticles ,in vivo activity ,Structure–activity relationship ,Animals ,Humans ,TLR4 ,Receptor ,HEK cells ,Animal ,Drug Discovery3003 Pharmaceutical Science ,Medicine (all) ,Macrophages ,Trehalose ,Biological activity ,Small molecule ,Endotoxins ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Lipid A ,Glucose ,HEK293 Cells ,MD-2 ,chemistry ,Biochemistry ,Molecular Medicine ,Signal transduction ,Glycolipids ,CD14 ,Human ,Signal Transduction - 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.
- Published
- 2014