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Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like receptor 4 (TLR4) modulators.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Nov 13; Vol. 57 (21), pp. 9105-23. Date of Electronic Publication: 2014 Oct 21. - Publication Year :
- 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.
- Subjects :
- Animals
Endotoxins antagonists & inhibitors
Glycolipids pharmacology
HEK293 Cells drug effects
Humans
Macrophages drug effects
Metal Nanoparticles chemistry
Mice, Inbred C57BL
Signal Transduction drug effects
Structure-Activity Relationship
Surface-Active Agents pharmacology
Toll-Like Receptor 4 agonists
Toll-Like Receptor 4 antagonists & inhibitors
Glucose analogs & derivatives
Glycolipids chemical synthesis
Surface-Active Agents chemical synthesis
Toll-Like Receptor 4 metabolism
Trehalose analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25268544
- Full Text :
- https://doi.org/10.1021/jm501182w