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

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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.
Keywords
LIPOPOLYSACCHARIDE (LPS)-BINDING PROTEIN, LIPID-A ANALOGS, RECEPTOR 4, BIOLOGICAL-ACTIVITIES, STRUCTURAL BASIS, VACCINE ADJUVANTS, CRYSTAL-STRUCTURE, LPS, CD14, RECOGNITION

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Citation

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Chicago
Cochet, Florent, Fabio A Facchini, Lenny Zaffaroni, Jean-Marc Billod, Helena Coelho, Aurora Holgado Munoz, Harald Braun, et al. 2019. “Novel Carboxylate-based Glycolipids : TLR4 Antagonism, MD-2 Binding and Self-assembly Properties.” Scientific Reports 9.
APA
Cochet, F., Facchini, F. A., Zaffaroni, L., Billod, J.-M., Coelho, H., Holgado Munoz, A., Braun, H., et al. (2019). Novel carboxylate-based glycolipids : TLR4 antagonism, MD-2 binding and self-assembly properties. SCIENTIFIC REPORTS, 9.
Vancouver
1.
Cochet F, Facchini FA, Zaffaroni L, Billod J-M, Coelho H, Holgado Munoz A, et al. Novel carboxylate-based glycolipids : TLR4 antagonism, MD-2 binding and self-assembly properties. SCIENTIFIC REPORTS. 2019;9.
MLA
Cochet, Florent et al. “Novel Carboxylate-based Glycolipids : TLR4 Antagonism, MD-2 Binding and Self-assembly Properties.” SCIENTIFIC REPORTS 9 (2019): n. pag. Print.
@article{8601565,
  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.},
  articleno    = {919},
  author       = {Cochet, Florent and Facchini, Fabio A and Zaffaroni, Lenny and Billod, Jean-Marc and Coelho, Helena and Holgado Munoz, Aurora and Braun, Harald and Beyaert, Rudi and Jerala, Roman and Jimenez-Barbero, Jesus and Martin-Santamaria, Sonsoles and Peri, Francesco},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  language     = {eng},
  pages        = {13},
  title        = {Novel carboxylate-based glycolipids : TLR4 antagonism, MD-2 binding and self-assembly properties},
  url          = {http://dx.doi.org/10.1038/s41598-018-37421-w},
  volume       = {9},
  year         = {2019},
}

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