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Sci Rep. 2019 Jan 29;9(1):919. doi: 10.1038/s41598-018-37421-w.

Novel carboxylate-based glycolipids: TLR4 antagonism, MD-2 binding and self-assembly properties.

Author information

1
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milano, Italy.
2
Department of Structural and Chemical Biology, Centro de Investigaciones Biologicas, CIB-CSIC, Ramiro de Maeztu, 9, 28040, Madrid, Spain.
3
Molecular Recognition & Host-Pathogen Interactions Programme, CIC bioGUNE, Bizkaia Technology Park, Building 801 A, 48170, Derio, Spain.
4
UCIBIO, REQUIMTE, Departamento de Quimica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal.
5
Department of Organic Chemistry II, Faculty of Science & Technology, University of the Basque Country, 48940, Leioa, Bizkaia, Spain.
6
Unit for Molecular Signal Transduction in Inflammation VIB-UGent Center for Inflammation Research, VIB Technologiepark 927, 9052, Zwijnaarde, Ghent, Belgium.
7
Department of Biomedical Molecular Biology, Ghent University Technologiepark 927, 9052, Zwijnaarde, Ghent, Belgium.
8
Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
9
Ikerbasque, Basque Foundation for Science, Maria Diaz de Haro 13, 48009, Bilbao, Spain.
10
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milano, Italy. francesco.peri@unimib.it.

Abstract

New monosaccharide-based lipid A analogues were rationally designed through MD-2 docking studies. A panel of compounds with two carboxylate groups as phosphates bioisosteres, was synthesized with the same glucosamine-bis-succinyl core linked to different unsaturated and saturated fatty acid chains. The binding of the synthetic compounds to purified, functional recombinant human MD-2 was studied by four independent methods. All compounds bound to MD-2 with similar affinities and inhibited in a concentration-dependent manner the LPS-stimulated TLR4 signaling in human and murine cells, while being inactive as TLR4 agonists when provided alone. A compound of the panel was tested in vivo and was not able to inhibit the production of proinflammatory cytokines in animals. This lack of activity is probably due to strong binding to serum albumin, as suggested by cell experiments in the presence of the serum. The interesting self-assembly property in solution of this type of compounds was investigated by computational methods and microscopy, and formation of large vesicles was observed by cryo-TEM microscopy.

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