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

Rodriguez Lavado, J., Sestito, S., Cighetti, R., Aguilar Moncayo, E., Oblak, A., Lainšček, D., et al. (2014). Trehalose- and glucose-derived glycoamphiphiles: Small-molecule and nanoparticle toll-like receptor 4 (TLR4) modulators. JOURNAL OF MEDICINAL CHEMISTRY, 57(21), 9105-9123 [10.1021/jm501182w].

Trehalose- and glucose-derived glycoamphiphiles: Small-molecule and nanoparticle toll-like receptor 4 (TLR4) modulators

SESTITO, STEFANIA ENZA
Secondo
;
CIGHETTI, ROBERTO;CALABRESE, VALENTINA
Penultimo
;
PERI, FRANCESCO
Ultimo
2014

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
Articolo in rivista - Articolo scientifico
Scientifica
Animals; Endotoxins; Glucose; Glycolipids; HEK293 Cells; Humans; Macrophages; Metal Nanoparticles; Mice, Inbred C57BL; Signal Transduction; Structure-Activity Relationship; Surface-Active Agents; Toll-Like Receptor 4; Trehalose; Molecular Medicine; Drug Discovery3003 Pharmaceutical Science; Medicine (all)
English
Rodriguez Lavado, J., Sestito, S., Cighetti, R., Aguilar Moncayo, E., Oblak, A., Lainšček, D., et al. (2014). Trehalose- and glucose-derived glycoamphiphiles: Small-molecule and nanoparticle toll-like receptor 4 (TLR4) modulators. JOURNAL OF MEDICINAL CHEMISTRY, 57(21), 9105-9123 [10.1021/jm501182w].
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
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/99985
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