6-Sulfo Sia-Gal as the Minimal Binding Epitope for Siglec-8, A Promising Target for Asthma

Session: 
S2.1 Oligosaccharide synthesis I
Code: 
FL2.1.4
Location (hall): 
Glucose
Start/end time: 
Monday, July 1, 2019 - 15:30 to 15:35
Bernadetta
Girardi

Benedetta Maria Girardi1Gabriele Conti1, Jonathan Cramer1, Blijke Kroezen1, Said Rabbani1, Daniel Ricklin1, Oliver Schwardt1, Beat Ernst1

1University of Basel, Basel, Switzerland

In this study we present the design, synthesis and biological evaluation of the Siglec-8 minimal binding epitope, the 6-Sulfo Sia-Gal disaccharide. 

Siglec-8 is an I-type lectin and member of the CD33-related Siglec family, which has recently gained attention as an interesting target for the treatment of inflammatory diseases. The protein is exclusively expressed on eosinophils and mast cells, playing a key role in the pathophysiology of asthma.[1] Asthma is the most common chronic lung disease worldwide, affecting more than 300 million people. Although its symptoms can be controlled in the majority of cases, no cure is currently available.[2] Targeting Siglec-8 with antibodies or glycan ligands results in apoptosis of eosinophils and inhibition of mast cells degranulation, suggesting Siglec-8 as a promising new pharmacological target for the treatment of asthma and other eosinophil or mast cell-related disorders.[3]

Recently, the NMR solution structure of the Siglec-8 lectin domain in complex with its preferred glycan epitope, the tetrasaccharide 6’-sulfo sialyl Lewisx, was published.[4] The key interactions involve two crucial salt bridges of the sialic acid carboxylate and the sulfate group in the 6’-position of D-Gal, whereas the L-Fuc- and D-GlcNAc-moieties show only minor contributions to binding. For these reasons the partial disaccharide structure 6-sulfo Sia-Gal was assumed to represent the minimal binding epitope for Siglec-8. We therefore synthesized the disaccharide fragment and evaluated its binding affinity to Siglec-8. In addition, a small library of bioisosteres of the disaccharide was synthesized and tested.

References: 
  1. Floyd, H.; Ni, J.; Cornish, A. L.; Zeng, Z.; Liu, D.; Carter, K. C.; Steel, J.; Crocker, P. R. Siglec-8. A novel eosinophil-specific member of the immunoglobulin superfamily. J. Biol. Chem. 2000, 275, 861-866. 
  2. Fahy, J. V. Type 2 inflammation in asthma - present in most, absent in many. Nat. Rev. Immunol. 2015, 15, 57-65.
  3. Kiwamoto, T.; Kawasaki, N.; Paulson, J. C.; Bochner, B. S. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol. Therapeut. 2012, 135, 327-336.
  4. Pröpster, J. M.; Yang, F.; Rabbani, S.; Ernst, B.; Allain, F. H.; Schubert, M. PNAS 2016, 113, E4170-4179.

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