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Exploring species-specificity in TLR4/MD-2 inhibition with amphiphilic lipid a mimicking glycolipids

Alessio Borio, Aurora Holgado Muñoz, Christina Passegger, Herbert Strobl, Rudi Beyaert (UGent) , Holger Heine and Alla Zamyatina
(2023) MOLECULES. 28(16).
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Abstract
The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex is a key receptor of the innate immune system and a major driver of inflammation that is responsible for the multifaceted defense response to Gram-negative infections. However, dysfunction in the tightly regulated mechanisms of TLR4-mediated signaling leads to the uncontrolled upregulation of local and systemic inflammation, often resulting in acute or chronic disease. Therefore, the TLR4/MD-2 receptor complex is an attractive target for the design and development of anti-inflammatory therapies which aim to control the unrestrained activation of TLR4-mediated signaling. Complex structure-activity relationships and species-specificity behind ligand recognition by the TLR4/MD-2 complex complicate the development of MD-2-specific TLR4 antagonists. The restriction of the conformational flexibility of the disaccharide polar head group is one of the key structural features of the newly developed lipid A-mimicking glycophospholipids, which are potential inhibitors of TLR4-mediated inflammation. Since phosphorylation has a crucial influence on MD-2-ligand interaction, glycolipids with variable numbers and positioning of phosphate groups were synthesized and evaluated for their ability to inhibit TLR4-mediated pro-inflammatory signaling in human and murine immune cells. A bis-phosphorylated glycolipid was found to have nanomolar antagonist activity on human TLR4 while acting as a partial agonist on murine TLR4. The glycolipid inhibited mTLR4/MD-2-mediated cytokine release, acting as an antagonist in the presence of lipopolysaccharide (LPS), but at the same time induced low-level cytokine production.
Keywords
carbohydrate-based inhibitors, lipopolysaccharide, inflammation, Toll-like receptor, carbohydrates, STRUCTURAL BASIS, RECEPTOR 4, HUMAN MD-2, BACTERIAL LIPOPOLYSACCHARIDES, ENDOTOXIC ACTIVITY, SEPSIS, TLR4, ANTAGONIST, TOLL-LIKE-RECEPTOR-4, ACTIVATION

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MLA
Borio, Alessio, et al. “Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid a Mimicking Glycolipids.” MOLECULES, vol. 28, no. 16, 2023, doi:10.3390/molecules28165948.
APA
Borio, A., Holgado Muñoz, A., Passegger, C., Strobl, H., Beyaert, R., Heine, H., & Zamyatina, A. (2023). Exploring species-specificity in TLR4/MD-2 inhibition with amphiphilic lipid a mimicking glycolipids. MOLECULES, 28(16). https://doi.org/10.3390/molecules28165948
Chicago author-date
Borio, Alessio, Aurora Holgado Muñoz, Christina Passegger, Herbert Strobl, Rudi Beyaert, Holger Heine, and Alla Zamyatina. 2023. “Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid a Mimicking Glycolipids.” MOLECULES 28 (16). https://doi.org/10.3390/molecules28165948.
Chicago author-date (all authors)
Borio, Alessio, Aurora Holgado Muñoz, Christina Passegger, Herbert Strobl, Rudi Beyaert, Holger Heine, and Alla Zamyatina. 2023. “Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid a Mimicking Glycolipids.” MOLECULES 28 (16). doi:10.3390/molecules28165948.
Vancouver
1.
Borio A, Holgado Muñoz A, Passegger C, Strobl H, Beyaert R, Heine H, et al. Exploring species-specificity in TLR4/MD-2 inhibition with amphiphilic lipid a mimicking glycolipids. MOLECULES. 2023;28(16).
IEEE
[1]
A. Borio et al., “Exploring species-specificity in TLR4/MD-2 inhibition with amphiphilic lipid a mimicking glycolipids,” MOLECULES, vol. 28, no. 16, 2023.
@article{01HDP104NXWZSQ5K3FER2A07FZ,
  abstract     = {{The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex is a key receptor of the innate immune system and a major driver of inflammation that is responsible for the multifaceted defense response to Gram-negative infections. However, dysfunction in the tightly regulated mechanisms of TLR4-mediated signaling leads to the uncontrolled upregulation of local and systemic inflammation, often resulting in acute or chronic disease. Therefore, the TLR4/MD-2 receptor complex is an attractive target for the design and development of anti-inflammatory therapies which aim to control the unrestrained activation of TLR4-mediated signaling. Complex structure-activity relationships and species-specificity behind ligand recognition by the TLR4/MD-2 complex complicate the development of MD-2-specific TLR4 antagonists. The restriction of the conformational flexibility of the disaccharide polar head group is one of the key structural features of the newly developed lipid A-mimicking glycophospholipids, which are potential inhibitors of TLR4-mediated inflammation. Since phosphorylation has a crucial influence on MD-2-ligand interaction, glycolipids with variable numbers and positioning of phosphate groups were synthesized and evaluated for their ability to inhibit TLR4-mediated pro-inflammatory signaling in human and murine immune cells. A bis-phosphorylated glycolipid was found to have nanomolar antagonist activity on human TLR4 while acting as a partial agonist on murine TLR4. The glycolipid inhibited mTLR4/MD-2-mediated cytokine release, acting as an antagonist in the presence of lipopolysaccharide (LPS), but at the same time induced low-level cytokine production.}},
  articleno    = {{5948}},
  author       = {{Borio, Alessio and Holgado Muñoz, Aurora and  Passegger, Christina and  Strobl, Herbert and Beyaert, Rudi and  Heine, Holger and  Zamyatina, Alla}},
  issn         = {{1420-3049}},
  journal      = {{MOLECULES}},
  keywords     = {{carbohydrate-based inhibitors,lipopolysaccharide,inflammation,Toll-like receptor,carbohydrates,STRUCTURAL BASIS,RECEPTOR 4,HUMAN MD-2,BACTERIAL LIPOPOLYSACCHARIDES,ENDOTOXIC ACTIVITY,SEPSIS,TLR4,ANTAGONIST,TOLL-LIKE-RECEPTOR-4,ACTIVATION}},
  language     = {{eng}},
  number       = {{16}},
  pages        = {{24}},
  title        = {{Exploring species-specificity in TLR4/MD-2 inhibition with amphiphilic lipid a mimicking glycolipids}},
  url          = {{http://doi.org/10.3390/molecules28165948}},
  volume       = {{28}},
  year         = {{2023}},
}
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