Autor: |
Horst, Prescher, Astrid, Schweizer, Martin, Frank, Elena, Kuhfeldt, Julia, Ring, Lars, Nitschke |
Rok vydání: |
2022 |
Předmět: |
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Zdroj: |
Journal of medicinal chemistry. 65(15) |
ISSN: |
1520-4804 |
Popis: |
Significant interest in the development of high-affinity ligands for Siglecs exists due to the various therapeutically relevant functions of these proteins. Here, we report a new strategy to develop and design Siglec ligands as disialyl-oligosaccharide mimetics exemplified on Siglec-2 (CD22). We report insights into development of dimeric ligands with high affinity and avidity to cell surface-expressed CD22, assay development, tool compounds, structure activity relationships, and biological data on calcium flux regulation in B-cells. The binding modes of selected ligands have been modeled based on state-of-the-art molecular dynamics simulations on the microsecond timescale, providing detailed views on ligand binding and opening a new perspective on drug design efforts for Siglecs. High-avidity dimeric ligands containing a linker opening the way towards bispecifics are presented as well. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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