Journal
CHEMBIOCHEM
Volume 15, Issue 2, Pages 250-258Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300588
Keywords
bioorganic chemistry; carbohydrates; drug design; molecular modeling; NMR
Funding
- US National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases(NIAID) [1R01AI059372]
- COST action [CM1102]
- Italian Ministry of Universities and Research (MIUR)
- Spanish MINECO [CTQ2012-32025, CTQ2011-22724]
- Universidad CEU San Pablo [PC14/2011, PC13/2012]
- European Commission
- Fondazione Cariplo [2010-0678]
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
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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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