Details

Autor(en) / Beteiligte

• Prescher, Horst
• Schweizer, Astrid
• Frank, Martin
• Kuhfeldt, Elena
• Ring, Julia
• Nitschke, Lars

Titel

Targeting Human CD22/Siglec‑2 with Dimeric Sialosides as Novel Oligosaccharide Mimetics

Ist Teil von

• Journal of medicinal chemistry, 2022-08, Vol.65 (15), p.10588-10610

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.