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A Potent Mimetic of the Siglec-8 Ligand 6'-Sulfo-Sialyl Lewisx.
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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ID |
4601118 |
Author(s) |
Kroezen, Blijke; Conti, Gabriele; Girardi, Benedetta; Cramer, Jonathan; Jiang, Xiaohua; Rabbani, Said; Müller, Jennifer; Kokot, Maja; Luisoni, Enrico; Ricklin, Daniel; Schwardt, Oliver; Ernst, Beat |
Author(s) at UniBasel |
Ernst, Beat Kroezen, Blijke Conti, Gabriele Girardi, Benedetta Maria Cramer, Jonathan Jiang, Xiaohua Rabbani, Said Ricklin, Daniel Schwardt, Oliver
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Year |
2020 |
Title |
A Potent Mimetic of the Siglec-8 Ligand 6'-Sulfo-Sialyl Lewisx. |
Journal |
ChemMedChem |
Volume |
15 |
Pages / Article-Number |
1706-1719 |
Keywords |
Siglec-8 * asthma * 6'-sulfo-sialyl Lewisx * glycosides * calorimetry |
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 systemsuch 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(1a) has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores in 6'-sulfo-sialyl Lewisx(1a) 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, usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. |
ISSN/ISBN |
1860-7187 |
Full Text on edoc |
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Digital Object Identifier DOI |
10.1002/cmdc.202000417 |
PubMed ID |
http://www.ncbi.nlm.nih.gov/pubmed/32744401 |
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20/04/2024
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