期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 19, 页码 8056-8071出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500946r
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资金
- Austrian Science Foundation [FWF P-22116]
- Austrian Science Fund (FWF) [P 22116] Funding Source: researchfish
The endotoxic portion of lipopolysaccharide (LPS), a glycophospholipid Lipid A, initiates the activation of the Toll-like Receptor 4 (TLR4)myeloid differentiation factor 2 (MD-2) complex, which results in pro-inflammatory immune signaling. To unveil the structural requirements for TLR4 center dot MD-2-specific ligands, we have developed conformationally restricted Lipid A mimetics wherein the flexible beta GlcN(1 -> 6)GlcN backbone of Lipid A is exchanged for a rigid trehalose-like alpha GlcN(1 <-> 1)alpha Man scaffold resembling the molecular shape of TLR4 center dot MD-2-bound E. coli Lipid A disclosed in the X-ray structure. A convergent synthetic route toward orthogonally protected alpha GlcN(1 <-> 1)alpha Man disaccharide has been elaborated. The alpha,alpha-(1 <-> 1) linkage was attained by the glycosylation of 2-N-carbamate-protected alpha-GlcN-lactol with N-phenyl-trifluoroacetimidate of 2-O-methylated mannose. Regioselective acylation with (R)-3-acyloxyacyl fatty acids and successive phosphorylation followed by global deprotection afforded bis- and monophosphorylated hexaacylated Lipid A mimetics. alpha GlcN(1 <-> 1)alpha Man-based Lipid A mimetics (alpha,alpha-GM-LAM) induced potent activation of NF-kappa B signaling in hTLR4/hMD-2/CD14-transfected HEK293 cells and robust LPS-like cytokines expression in macrophages and dendritic cells. Thus, restricting the conformational flexibility of Lipid A by fixing the molecular shape of its carbohydrate backbone in the agonistic conformation attained by a rigid alpha GlcN(1 <-> 1)alpha Man scaffold represents an efficient approach toward powerful and adjustable TLR4 activation.
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