title: Modulation of CD14 and TLR4·MD-2 activities by a synthetic lipid A mimetic.
abstract: 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 TLR4-related syndromes.
authors: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano (Italy).
authors: Roberto
authors: R
authors: Cighetti
authors: Carlotta
authors: C
authors: Ciaramelli
authors: Stefania Enza
authors: SE
authors: Sestito
authors: Ivan
authors: I
authors: Zanoni
authors: Łukasz
authors: Ł
authors: Kubik
authors: Ana
authors: A
authors: Ardá-Freire
authors: Valentina
authors: V
authors: Calabrese
authors: Francesca
authors: F
authors: Granucci
authors: Roman
authors: R
authors: Jerala
authors: Sonsoles
authors: S
authors: Martín-Santamaría
authors: Jesus
authors: J
authors: Jiménez-Barbero
authors: Francesco
authors: F
authors: Peri
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008050:Lipid A / Q000737:chemistry*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D009005:Monosaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C495377:LY96 protein, human; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D009005:Monosaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4
keywords: NMR; bioorganic chemistry; carbohydrates; drug design; molecular modeling