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Disaccharide-based anionic amphiphiles as potent inhibitors of lipopolysaccharide-induced inflammation

(2018) CHEMMEDCHEM. 13(21). p.2317-2331
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Abstract
Despite significant advances made in the last decade in the understanding of molecular mechanisms of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide. Toll-like receptor 4 (TLR4)-a transmembrane pattern-recognition receptor responsible for propagating the immediate immune response to Gram-negative bacterial infection-plays a central role in the pathogenesis of sepsis and chronic inflammation-related disorders. TLR4 is complexed with the lipopolysaccharide (LPS)-sensing protein myeloid differentiation-2 (MD-2) which represents a preferred target for establishing new anti-inflammatory treatment strategies. Herein we report the development, facile synthesis, and biological evaluation of novel disaccharide-based TLR4-MD-2 antagonists with potent anti-endotoxic activity at micromolar concentrations. A series of synthetic anionic glycolipids entailing amide-linked beta-ketoacyl lipid residues was prepared in a straightforward manner by using a single orthogonally protected nonreducing diglucosamine scaffold. Suppression of the LPS-induced release of interleukin-6 and tumor necrosis factor was monitored and confirmed in human immune cells (MNC and THP1) and mouse macrophages. Structure-activity relationship studies and molecular dynamics simulations revealed the structural basis for the high-affinity interaction between anionic glycolipids and MD-2, and highlighted two compounds as leads for the development of potential anti-inflammatory therapeutics.
Keywords
KETO-ENOL-TAUTOMERISM, TOLL-LIKE RECEPTORS, STRUCTURAL BASIS, ENDOTOXIN, ANTAGONIST, LIPID-A, PROPOSED STRUCTURE, TLR4-MD-2 COMPLEX, BINDING-AFFINITY, INNATE IMMUNITY, SEVERE SEPSIS, drug discoveryantisepsis, carbohydrates, glycolipids, innate immunity

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Citation

Please use this url to cite or link to this publication:

MLA
Borio, Alessio et al. “Disaccharide-based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide-induced Inflammation.” CHEMMEDCHEM 13.21 (2018): 2317–2331. Print.
APA
Borio, A., Holgado Munoz, A., Antonio Garate, J., Beyaert, R., Heine, H., & Zamyatina, A. (2018). Disaccharide-based anionic amphiphiles as potent inhibitors of lipopolysaccharide-induced inflammation. CHEMMEDCHEM, 13(21), 2317–2331.
Chicago author-date
Borio, Alessio, Aurora Holgado Munoz, Jose Antonio Garate, Rudi Beyaert, Holger Heine, and Alla Zamyatina. 2018. “Disaccharide-based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide-induced Inflammation.” Chemmedchem 13 (21): 2317–2331.
Chicago author-date (all authors)
Borio, Alessio, Aurora Holgado Munoz, Jose Antonio Garate, Rudi Beyaert, Holger Heine, and Alla Zamyatina. 2018. “Disaccharide-based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide-induced Inflammation.” Chemmedchem 13 (21): 2317–2331.
Vancouver
1.
Borio A, Holgado Munoz A, Antonio Garate J, Beyaert R, Heine H, Zamyatina A. Disaccharide-based anionic amphiphiles as potent inhibitors of lipopolysaccharide-induced inflammation. CHEMMEDCHEM. 2018;13(21):2317–31.
IEEE
[1]
A. Borio, A. Holgado Munoz, J. Antonio Garate, R. Beyaert, H. Heine, and A. Zamyatina, “Disaccharide-based anionic amphiphiles as potent inhibitors of lipopolysaccharide-induced inflammation,” CHEMMEDCHEM, vol. 13, no. 21, pp. 2317–2331, 2018.
@article{8600879,
  abstract     = {Despite significant advances made in the last decade in the understanding of molecular mechanisms of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide. Toll-like receptor 4 (TLR4)-a transmembrane pattern-recognition receptor responsible for propagating the immediate immune response to Gram-negative bacterial infection-plays a central role in the pathogenesis of sepsis and chronic inflammation-related disorders. TLR4 is complexed with the lipopolysaccharide (LPS)-sensing protein myeloid differentiation-2 (MD-2) which represents a preferred target for establishing new anti-inflammatory treatment strategies. Herein we report the development, facile synthesis, and biological evaluation of novel disaccharide-based TLR4-MD-2 antagonists with potent anti-endotoxic activity at micromolar concentrations. A series of synthetic anionic glycolipids entailing amide-linked beta-ketoacyl lipid residues was prepared in a straightforward manner by using a single orthogonally protected nonreducing diglucosamine scaffold. Suppression of the LPS-induced release of interleukin-6 and tumor necrosis factor was monitored and confirmed in human immune cells (MNC and THP1) and mouse macrophages. Structure-activity relationship studies and molecular dynamics simulations revealed the structural basis for the high-affinity interaction between anionic glycolipids and MD-2, and highlighted two compounds as leads for the development of potential anti-inflammatory therapeutics.},
  author       = {Borio, Alessio and Holgado Munoz, Aurora and Antonio Garate, Jose and Beyaert, Rudi and Heine, Holger and Zamyatina, Alla},
  issn         = {1860-7179},
  journal      = {CHEMMEDCHEM},
  keywords     = {KETO-ENOL-TAUTOMERISM,TOLL-LIKE RECEPTORS,STRUCTURAL BASIS,ENDOTOXIN,ANTAGONIST,LIPID-A,PROPOSED STRUCTURE,TLR4-MD-2 COMPLEX,BINDING-AFFINITY,INNATE IMMUNITY,SEVERE SEPSIS,drug discoveryantisepsis,carbohydrates,glycolipids,innate immunity},
  language     = {eng},
  number       = {21},
  pages        = {2317--2331},
  title        = {Disaccharide-based anionic amphiphiles as potent inhibitors of lipopolysaccharide-induced inflammation},
  url          = {http://dx.doi.org/10.1002/cmdc.201800505},
  volume       = {13},
  year         = {2018},
}

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