A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx |
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Authors: | Dr Blijke S Kroezen Gabriele Conti Benedetta Girardi Dr Jonathan Cramer Dr Xiaohua Jiang Dr Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof Daniel Ricklin Dr Oliver Schwardt Prof Beat Ernst |
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Affiliation: | Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland |
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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 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. |
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Keywords: | Siglec-8 asthma 6’-sulfo-sialyl Lewisx glycosides calorimetry |
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