Synthetic 1,1΄-linked disaccharide – based glycolipids for immunomodulation

Session: 
S10.1 Lipopolysaccharides
Code: 
OL10.1.2
Location (hall): 
Glucose
Start/end time: 
Thursday, July 4, 2019 - 17:30 to 17:45
Alla
Zamyatina

Alla Zamyatina1

1University of Natural Resources and Life Sciences, Department of Chemistry, Vienna, Austria

Immunomodulation is a promising strategy for therapy of acute and chronic diseases ranging from antibiotic-resistant infections to autoimmune disorders and cancer. We aim at coordinating the immune response to infection and chronic inflammation by targeting the lipopolysaccharide (LPS)-sensing innate immune receptors Toll-like receptor 4 (TLR4) and caspase-4 (as well as its murine homolog caspase-11). The transmembrane TLR4 complex and the cytosolic cysteine protease caspase-4 are responsible for propagating the immediate immune response to Gram-negative infection which is aimed at bacterial clearance. Dysregulated TLR4 and caspase-4 signaling is involved in the pathogenesis of numerous chronic and acute inflammatory disorders; besides, activation of TLR4 and caspase-4/11 plays the central role in the initiation and pathophysiology of sepsis syndrome.[1-3] Sepsis is increasingly reputed as the final common pathway to death from infection and remains the leading cause of mortality in intensive care units. Recent studies revealed that the deficiency of the TLR4-driven inflammation, rather than inefficient pathogen clearance, is responsible for the severity of Gram-negative sepsis. It has been also recognized that the progression of many chronic and autoimmune diseases is related to non-resolving inflammation, which underscores TLR4 and caspase-4 directed immunotherapy as promising approach for treatment of variety of disorders. 

Using crystal-structure based design we developed unique 1,1′-linked disaccharide based glycolipids as TLR4 and caspase-4/11 ligands with pico- to nanomolar affinity for respective innate immune receptors. We synthesized a library of anionic glycolipids derived from β,α-1,1´-, α,α-1,1´ and β,β-1,1´ - linked disaccharide scaffolds which can either potently induce the TLR4-mediated intracellular signaling, or inhibit the TLR4- and/or caspase-4/11 mediated inflammation and fully block the endotoxic action of LPS. We found that the specific 3D-molecular shape of the non-reducing disaccharide scaffold (which is inflicted by the anomeric configuration around the rigid 1,1΄-glycosidic linkage: αα, ββ, or βα) is decisive for the expression of agonist or antagonist activities.[4,5] 

The chemistry behind the synthesis of 1,1´-linked disaccharide-derived innate immune modulators involves the challenging stereoselective 1,1´-glycosylation to attain fully orthogonally protected non-symmetrical disaccharide scaffolds having β,α-1,1´-, α,α-1,1´ or β,β-1,1´ configuration. Matching the reactivities of glycosyl donor and acceptor pairs by varying the protecting group pattern and employing conformationally locked hemiacetal-acceptors was decisive for achieving high glycosylation stereoselectivity and yields. The disaccharide scaffolds were subsequently decorated by phosphate groups and long-chain β-hydroxy-, β-acyloxyacyl or β-keto- lipid residues of variable length. 

Manipulating the 3D-structure and the phosphorylation status of the disaccharide-derived anionic glycolipids allowed for discovery of first caspase-4/11 antagonists as potential anti-sepsis drug candidates and for development of powerful inducers of the TLR4 signaling and caspase-4/11 activation as potential immunotherapeutics and vaccine adjuvants.

Acknowlegements

Financial support by Austrian Science Fund (Grant FWF P-28915) is gratefully acknowledged.

References: 
  1. Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 5, 373-384.
  2. Shi, J.; Zhao, Y.; Wang, Y.; Gao, W.; Ding, J.; Li, P.; Hu, L.; Shao, F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014, 514, 187-192.
  3. Hagar, J. A.; Powell, D. A.; Aachoui, Y.; Ernst, R. K.; Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 2013, 341, 1250-1253.
  4. 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. Chem. Sci. 2018, 16, 3957-3963.
  5. Borio, A.; Holgado, A.; Garate, J. A.; Beyaert, R.; Heine, H.; Zamyatina, A. Disaccharide-based anionic amphiphiles as potent inhibitors of lipopolysaccharide-induced inflammation. ChemMedChem 2018, 13, 2317-2331.

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