A Potent Mimetic of the Siglec‐8 Ligand 6’‐Sulfo‐Sialyl Lewisx

Abstract 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 Lewis x 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 Lewis x 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.