Modulation of CD14 and TLR4⋅MD-2 Activities by a Synthetic Lipid A Mimetic

Authors

  • Roberto Cighetti,

    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
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  • Carlotta Ciaramelli,

    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
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  • Stefania Enza Sestito,

    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
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  • Dr. Ivan Zanoni,

    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
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  • Łukasz Kubik,

    1. Department of Chemistry and Biochemistry, Faculty of Pharmacy, Universidad CEU San Pablo, Urb. Montepríncipe, 28668 Boadilla del Monte, Madrid (Spain)
    2. Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gen. Józefa Hallera 107 Street, 80-416 Gdańsk (Poland)
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  • Dr. Ana Ardá-Freire,

    1. Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CIB-CSIC C/, Ramiro de Maeztu 9, 28040 Madrid (Spain))
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  • Dr. Valentina Calabrese,

    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
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  • Francesca Granucci,

    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
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  • Prof. Roman Jerala,

    1. Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana (Slovenia
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  • Prof. Sonsoles Martín-Santamaría,

    1. Department of Chemistry and Biochemistry, Faculty of Pharmacy, Universidad CEU San Pablo, Urb. Montepríncipe, 28668 Boadilla del Monte, Madrid (Spain)
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  • Prof. Jesus Jiménez-Barbero,

    1. Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CIB-CSIC C/, Ramiro de Maeztu 9, 28040 Madrid (Spain))
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  • Prof. Francesco Peri

    Corresponding author
    1. Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
    • Department of Biotechnology and Biosciences, University of Milano–Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)

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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-2TLR4 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.

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