Trehalose- and Glucose-Derived Glycoamphiphiles: Small-Molecule and Nanoparticle Toll-Like Receptor 4 (TLR4) Modulators

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• 作者：Julio Rodriguez Lavado ; Stefania E. Sestito ; Roberto Cighetti ; Eva M. Aguilar Moncayo ; Alja Oblak ; Du拧ko Lain拧膷ek ; Jos茅 Luis Jim茅nez Blanco ; Jos茅 Manuel Garc铆a Fern谩ndez ; Carmen Ortiz Mellet ; Roman Jerala ; Valentina Calabrese ; Francesco Peri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：57
• 期：21
• 页码：9105-9123
• 全文大小：786K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.