A Potent Mimetic of the Siglec-8 Ligand 6'-Sulfo-Sialyl Lewisx.
Blijke S KroezenGabriele ContiBenedetta GirardiJonathan CramerXiaohua JiangSaid RabbaniJennifer MüllerMaja KokotEnrico LuisoniDaniel RicklinOliver SchwardtBeat ErnstPublished in: ChemMedChem (2020)
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6'-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6'-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.
Keyphrases
- oxidative stress
- single cell
- chronic obstructive pulmonary disease
- cell death
- lung function
- high resolution
- dna binding
- binding protein
- cell therapy
- endoplasmic reticulum stress
- high throughput
- mesenchymal stem cells
- mass spectrometry
- transcription factor
- signaling pathway
- air pollution
- capillary electrophoresis
- low density lipoprotein