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Chemo-enzymatic Synthesis of N-glycans for Array Development and HIV Antibody Profiling
Published on: February 5, 2018
Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics
Florian Adanitsch1, Jianjin Shi2, Feng Shao2
1Department of Chemistry , University of Natural Resources and Life Sciences , Muthgasse 18 , A-1190 Vienna , Austria .
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 α,α-(1↔1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-independent and adjustable TLR4-mediated NF-κB 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.
Insights
Researchers developed novel glycan-based compounds that activate Toll-like receptor 4 (TLR4) for immune responses while preventing cell death from caspase-4/11 activation. This offers a new strategy for safe vaccine adjuvants and immunotherapeutics.
Area of Science:
- Immunology
- Molecular Biology
- Synthetic Chemistry
Background:
- Lipopolysaccharide (LPS) from Gram-negative bacteria activates Toll-like receptor 4 (TLR4), crucial for immunity, but also caspase-4/11, leading to pyroptosis and sepsis.
- Precisely controlling TLR4 activation without inducing detrimental caspase-4/11 activity remains a challenge.
- Understanding the structural basis of LPS interaction with caspase-4/11 is critical for therapeutic development.
Purpose of the Study:
- To discover potent immunostimulants that selectively modulate TLR4 signaling.
- To investigate the structural mechanisms underlying caspase-4/11 activation by LPS.
- To develop a chemical strategy for controlled TLR4-mediated cytokine release, independent of caspase-11 protease activity.
Main Methods:
- Design and synthesis of novel glycan-based immunostimulants mimicking LPS.
- Affinity determination for TLR4 and assessment of caspase-4/11 interaction and oligomerization.
- Crystal structure-based design and advanced synthetic chemistry to create molecular probes.
- Evaluation of TLR4-mediated NF-κB signaling and caspase-11 protease activity.
Main Results:
- Discovery of potent glycan-based compounds with picomolar affinity for TLR4.
- These compounds induce caspase-4/11 oligomerization but abolish caspase-11 protease activity.
- The rigid, twisted structure of the synthetic glycolipids enables tunable, species-independent TLR4 signaling and modulated caspase-4/11 activation.
- A chemical strategy was established for dissociating TLR4-mediated cytokine release from caspase-11 protease activity.
Conclusions:
- Novel synthetic anionic glycolipids offer a means to controllably activate TLR4-mediated immunity.
- These compounds provide a platform for dissecting the structural basis of caspase-4/11 activation.
- This approach paves the way for developing safer vaccine adjuvants and immunotherapeutics by decoupling beneficial immune stimulation from cell death pathways.
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