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Anti-endotoxic activity and structural basis for human MD-2∙TLR4 antagonism of tetraacylated lipid A mimetics based on βGlcN(l↔l)αGlcN scaffold

(2015) INNATE IMMUNITY. 21(5). p.490-503
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Abstract
Interfering with LPS binding by the co-receptor protein myeloid differentiation factor 2 (MD-2) represents a useful approach for down-regulation of MD-2.TLR4-mediated innate immune signaling, which is implicated in the pathogenesis of a variety of human diseases, including sepsis syndrome. The antagonistic activity of a series of novel synthetic tetraacylated bis-phosphorylated glycolipids based on the GlcN(11)GlcN scaffold was assessed in human monocytic macrophage-like cell line THP-1, dendritic cells and human epithelial cells. Two compounds were shown to inhibit efficiently the LPS-induced inflammatory signaling by down-regulation of the expression of TNF-, IL-6, IL-8, IL-10 and IL-12 to background levels. The binding of the tetraacylated by (R)-3-hydroxy-fatty acids (2xC(12,) 2xC(14)), 4,4-bisphosphorylated GlcN(11)GlcN-based lipid A mimetic DA193 to human MD-2 was calculated to be 20-fold stronger than that of Escherichia coli lipid A. Potent antagonistic activity was related to a specific molecular shape induced by the ,(11)-diglucosamine backbone. Co-planar' relative arrangement of the GlcN rings was inflicted by the double exo-anomeric conformation around both glycosidic torsions in the rigid ,(11) linkage, which was ascertained using NOESY NMR experiments and confirmed by molecular dynamics simulation. In contrast to the native lipid A ligands, the binding affinity of GlcN(11)GlcN-based lipid A mimetics to human MD-2 was independent on the orientation of the diglucosamine backbone of the synthetic antagonist within the binding pocket of hMD-2 (rotation by 180 degrees) allowing for two equally efficient binding modes as shown by molecular dynamics simulation.
Keywords
lipid A, lipopolysaccharide, glycolipids, Antagonist, MD-2, molecular dynamics simulation, NMR, Toll-like receptor 4, MOLECULAR-DYNAMICS, DENDRITIC CELLS, CONFORMATIONAL BEHAVIOR, LIPOPOLYSACCHARIDE RECOGNITION, TLR4-MD-2 COMPLEX, BINDING-AFFINITY, C-GLYCOSYL, RECEPTOR 4, ACTIVATION, NMR

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Citation

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Chicago
Garate, Jose Antonio, Johannes Stöckl, María del Carmen Fernández-Alonso, Daniel Artner, Mira Haegman, Chris Oostenbrink, Jesús Jiménez-Barbero, et al. 2015. “Anti-endotoxic Activity and Structural Basis for Human MD-2∙TLR4 Antagonism of Tetraacylated Lipid A Mimetics Based on βGlcN(l↔l)αGlcN Scaffold.” Innate Immunity 21 (5): 490–503.
APA
Garate, J. A., Stöckl, J., Fernández-Alonso, M. del C., Artner, D., Haegman, M., Oostenbrink, C., Jiménez-Barbero, J., et al. (2015). Anti-endotoxic activity and structural basis for human MD-2∙TLR4 antagonism of tetraacylated lipid A mimetics based on βGlcN(l↔l)αGlcN scaffold. INNATE IMMUNITY, 21(5), 490–503.
Vancouver
1.
Garate JA, Stöckl J, Fernández-Alonso M del C, Artner D, Haegman M, Oostenbrink C, et al. Anti-endotoxic activity and structural basis for human MD-2∙TLR4 antagonism of tetraacylated lipid A mimetics based on βGlcN(l↔l)αGlcN scaffold. INNATE IMMUNITY. 2015;21(5):490–503.
MLA
Garate, Jose Antonio, Johannes Stöckl, María del Carmen Fernández-Alonso, et al. “Anti-endotoxic Activity and Structural Basis for Human MD-2∙TLR4 Antagonism of Tetraacylated Lipid A Mimetics Based on βGlcN(l↔l)αGlcN Scaffold.” INNATE IMMUNITY 21.5 (2015): 490–503. Print.
@article{6849714,
  abstract     = {Interfering with LPS binding by the co-receptor protein myeloid differentiation factor 2 (MD-2) represents a useful approach for down-regulation of MD-2.TLR4-mediated innate immune signaling, which is implicated in the pathogenesis of a variety of human diseases, including sepsis syndrome. The antagonistic activity of a series of novel synthetic tetraacylated bis-phosphorylated glycolipids based on the GlcN(11)GlcN scaffold was assessed in human monocytic macrophage-like cell line THP-1, dendritic cells and human epithelial cells. Two compounds were shown to inhibit efficiently the LPS-induced inflammatory signaling by down-regulation of the expression of TNF-, IL-6, IL-8, IL-10 and IL-12 to background levels. The binding of the tetraacylated by (R)-3-hydroxy-fatty acids (2xC(12,) 2xC(14)), 4,4-bisphosphorylated GlcN(11)GlcN-based lipid A mimetic DA193 to human MD-2 was calculated to be 20-fold stronger than that of Escherichia coli lipid A. Potent antagonistic activity was related to a specific molecular shape induced by the ,(11)-diglucosamine backbone. Co-planar' relative arrangement of the GlcN rings was inflicted by the double exo-anomeric conformation around both glycosidic torsions in the rigid ,(11) linkage, which was ascertained using NOESY NMR experiments and confirmed by molecular dynamics simulation. In contrast to the native lipid A ligands, the binding affinity of GlcN(11)GlcN-based lipid A mimetics to human MD-2 was independent on the orientation of the diglucosamine backbone of the synthetic antagonist within the binding pocket of hMD-2 (rotation by 180 degrees) allowing for two equally efficient binding modes as shown by molecular dynamics simulation.},
  author       = {Garate, Jose Antonio and St{\"o}ckl, Johannes and Fern{\'a}ndez-Alonso, Mar{\'i}a del Carmen and Artner, Daniel and Haegman, Mira and Oostenbrink, Chris and Jim{\'e}nez-Barbero, Jes{\'u}s and Beyaert, Rudi and Heine, Holger and Kosma, Paul and Zamyatina, Alla},
  issn         = {1753-4259},
  journal      = {INNATE IMMUNITY},
  keyword      = {lipid A,lipopolysaccharide,glycolipids,Antagonist,MD-2,molecular dynamics simulation,NMR,Toll-like receptor 4,MOLECULAR-DYNAMICS,DENDRITIC CELLS,CONFORMATIONAL BEHAVIOR,LIPOPOLYSACCHARIDE RECOGNITION,TLR4-MD-2 COMPLEX,BINDING-AFFINITY,C-GLYCOSYL,RECEPTOR 4,ACTIVATION,NMR},
  language     = {eng},
  number       = {5},
  pages        = {490--503},
  title        = {Anti-endotoxic activity and structural basis for human MD-2\unmatched{2219}TLR4 antagonism of tetraacylated lipid A mimetics based on \ensuremath{\beta}GlcN(l\ensuremath{\leftrightarrow}l)\ensuremath{\alpha}GlcN scaffold},
  url          = {http://dx.doi.org/10.1177/1753425914550426},
  volume       = {21},
  year         = {2015},
}

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