Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4.
Tetra-acylated lipid As derived from Porphyromonas gingivalis LPS have been synthesized using a key disaccharide intermediate functionalized with levulinate (Lev), allyloxycarbonate (Alloc) and anomeric dimethylthexylsilyl (TDS) as orthogonal protecting groups and 9-fluorenylmethoxycarbamate (Fmoc) and azido as amino protecting groups. Furthermore, an efficient cross-metathesis has been employed for the preparation of the unusual branched R-(3)-hydroxy-13-methyltetradecanic acid and (R)-3-hexadecanoyloxy-15-methylhexadecanoic acid of P. gingivalis lipid A. Biological studies have shown that the synthetic lipid As cannot activate human and mouse TLR2 and TLR4 to produce cytokines. However, it has been found that the compounds are potent antagonist of cytokine secretion by human monocytic cells induced by enteric LPS.
Zhang
Yanghui
Y
Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA.
Gaekwad
Jidnyasa
J
Wolfert
Margreet A
MA
Boons
Geert-Jan
GJ
D000215:Acylation; D000818:Animals; D002460:Cell Line; D004926:Escherichia coli / Q000737:chemistry; D006801:Humans; D008050:Lipid A / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D016966:Porphyromonas gingivalis / Q000737:chemistry*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008050:Lipid A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4