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Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics

(2018) CHEMICAL SCIENCE. 9(16). p.3957-3963
Author
Organization
Abstract
Gram-negative bacterial lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) mediated pro-inflammatory signaling plays a key role in immunoprotection against infectious challenges and boosts adaptive immunity, whereas the activation of the cytosolic LPS receptor caspase-4/11 leads to cell death by pyroptosis and is deeply implicated in the development of sepsis. Despite tremendous advances in the understanding of the LPS-TLR4 interaction, predictably regulated TLR4 activation has not yet been achieved. The structural basis for the induction of caspase-4/11 protease activity by LPS is currently unknown. The modulation of innate and adaptive immune responses through the controlled induction of TLR4 signaling without triggering caspase-4/11 activity would open novel perspectives in the development of safe vaccine adjuvants and immunotherapeutics. We report the discovery of highly potent glycan-based immunostimulants with picomolar affinity for TLR4 which interact with caspase-4/11 and promote caspase-4/11 oligomerization while abolishing caspase-11 protease activity. The rigidity and twisted molecular shape of the alpha,alpha-(1 <--> 1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-independent and adjustable TLR4-mediated NF-kappa B signaling and the modulation of caspase-4/11 activation. By the use of crystal structure based design and advanced synthetic chemistry we created a set of versatile probes for studying the structural basis of caspase-4/11 activation and established a chemical strategy for controllable TLR4 mediated cytokine release which is dissociable from the induction of caspase-11 protease activity.
Keywords
TOLL-LIKE RECEPTORS, MONOPHOSPHORYL-LIPID-A, INNATE IMMUNE RECEPTORS, INFLAMMATORY CASPASES, STRUCTURAL BASIS, VACCINE ADJUVANT, TLR4/MD-2, ACTIVATION, ALZHEIMERS-DISEASE, INTRACELLULAR LPS, ENDOTOXIN

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Citation

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MLA
Adanitsch, Florian et al. “Synthetic Glycan-based TLR4 Agonists Targeting Caspase-4/11 for the Development of Adjuvants and Immunotherapeutics.” CHEMICAL SCIENCE 9.16 (2018): 3957–3963. Print.
APA
Adanitsch, F., Shi, J., Shao, F., Beyaert, R., Heine, H., & Zamyatina, A. (2018). Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics. CHEMICAL SCIENCE, 9(16), 3957–3963.
Chicago author-date
Adanitsch, Florian, Jianjin Shi, Feng Shao, Rudi Beyaert, Holger Heine, and Alla Zamyatina. 2018. “Synthetic Glycan-based TLR4 Agonists Targeting Caspase-4/11 for the Development of Adjuvants and Immunotherapeutics.” Chemical Science 9 (16): 3957–3963.
Chicago author-date (all authors)
Adanitsch, Florian, Jianjin Shi, Feng Shao, Rudi Beyaert, Holger Heine, and Alla Zamyatina. 2018. “Synthetic Glycan-based TLR4 Agonists Targeting Caspase-4/11 for the Development of Adjuvants and Immunotherapeutics.” Chemical Science 9 (16): 3957–3963.
Vancouver
1.
Adanitsch F, Shi J, Shao F, Beyaert R, Heine H, Zamyatina A. Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics. CHEMICAL SCIENCE. 2018;9(16):3957–63.
IEEE
[1]
F. Adanitsch, J. Shi, F. Shao, R. Beyaert, H. Heine, and A. Zamyatina, “Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics,” CHEMICAL SCIENCE, vol. 9, no. 16, pp. 3957–3963, 2018.
@article{8582072,
  abstract     = {Gram-negative bacterial lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) mediated pro-inflammatory signaling plays a key role in immunoprotection against infectious challenges and boosts adaptive immunity, whereas the activation of the cytosolic LPS receptor caspase-4/11 leads to cell death by pyroptosis and is deeply implicated in the development of sepsis. Despite tremendous advances in the understanding of the LPS-TLR4 interaction, predictably regulated TLR4 activation has not yet been achieved. The structural basis for the induction of caspase-4/11 protease activity by LPS is currently unknown. The modulation of innate and adaptive immune responses through the controlled induction of TLR4 signaling without triggering caspase-4/11 activity would open novel perspectives in the development of safe vaccine adjuvants and immunotherapeutics. We report the discovery of highly potent glycan-based immunostimulants with picomolar affinity for TLR4 which interact with caspase-4/11 and promote caspase-4/11 oligomerization while abolishing caspase-11 protease activity. The rigidity and twisted molecular shape of the alpha,alpha-(1 <--> 1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-independent and adjustable TLR4-mediated NF-kappa B signaling and the modulation of caspase-4/11 activation. By the use of crystal structure based design and advanced synthetic chemistry we created a set of versatile probes for studying the structural basis of caspase-4/11 activation and established a chemical strategy for controllable TLR4 mediated cytokine release which is dissociable from the induction of caspase-11 protease activity.},
  author       = {Adanitsch, Florian and Shi, Jianjin and Shao, Feng and Beyaert, Rudi and Heine, Holger and Zamyatina, Alla},
  issn         = {2041-6520},
  journal      = {CHEMICAL SCIENCE},
  keywords     = {TOLL-LIKE RECEPTORS,MONOPHOSPHORYL-LIPID-A,INNATE IMMUNE RECEPTORS,INFLAMMATORY CASPASES,STRUCTURAL BASIS,VACCINE ADJUVANT,TLR4/MD-2,ACTIVATION,ALZHEIMERS-DISEASE,INTRACELLULAR LPS,ENDOTOXIN},
  language     = {eng},
  number       = {16},
  pages        = {3957--3963},
  title        = {Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics},
  url          = {http://dx.doi.org/10.1039/c7sc05323a},
  volume       = {9},
  year         = {2018},
}

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