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Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic
Author(s) -
Cighetti Roberto,
Ciaramelli Carlotta,
Sestito Stefania Enza,
Zai Ivan,
Kubik Łukasz,
ArdáFreire Ana,
Calabrese Valentina,
Granucci Francesca,
Jerala Roman,
MartínSantamaría Sonsoles,
JiménezBarbero Jesus,
Peri Francesco
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201300588
Subject(s) - chemistry , internalization , tlr4 , lipid a , hek 293 cells , biochemistry , cd14 , monosaccharide , receptor , lipopolysaccharide , biology , endocrinology
Monosaccharide lipid A mimetics based on a glucosamine core linked to two fatty acid chains and bearing one or two phosphate groups have been synthesized. Compounds 1 and 2 , each with one phosphate group, were practically inactive in inhibiting LPS‐induced TLR4 signaling and cytokine production in HEK‐blue cells and murine macrophages, but compound 3 , with two phosphate groups, was found to be active in efficiently inhibiting TLR4 signal in both cell types. The direct interaction between compound 3 and the MD‐2 coreceptor was investigated by NMR spectroscopy and molecular modeling/docking analysis. This compound also interacts directly with the CD14 receptor, stimulating its internalization by endocytosis. Experiments on macrophages show that the effect on CD14 reinforces the activity on MD‐2 ⋅ TLR4 because compound 3 's activity is higher when CD14 is important for TLR4 signaling (i.e., at low LPS concentration). The dual targeting of MD‐2 and CD14, accompanied by good solubility in water and lack of toxicity, suggests the use of monosaccharide 3 as a lead compound for the development of drugs directed against TLR4related syndromes.