期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 72, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2022.116974
关键词
Multivalent ligand; Glycocluster; Galectin-3; Cyclodextrin scaffold; Tn antigen; TF antigen
资金
- Dr. Jared Orwenyo
A facile synthesis of beta-cyclodextrin-based multivalent ligands containing Tn and TF antigens was reported. These synthetic multivalent glycan ligands demonstrated enhanced binding affinity and clustering effect in binding to human Gal-3. The GalNAc-containing heptavalent ligand showed the highest affinity and the synthetic ligands could efficiently inhibit Gal-3 binding to human airway epithelial cells.
Human galectin 3 (Gal-3) has been implicated to play important roles in different biological recognition pro-cesses such as tumor growth and cancer metastasis. High-affinity Gal-3 ligands are desirable for functional studies and as inhibitors for potential therapeutic development. We report here a facile synthesis of beta-cyclo-dextrin (CD)-based Tn and TF antigen-containing multivalent ligands via a click reaction. Binding studies indicated that the synthetic multivalent glycan ligands demonstrated a clear clustering effect in binding to human Gal-3, with up to 153-fold enhanced relative affinity in comparison with the monomeric glycan ligand. The GalNAc (Tn antigen) containing heptavalent ligand showed the highest affinity for human Gal-3 among the synthetic ligands tested, with an EC50 of 1.4 ??M in binding to human Gal-3. A cell-based assay revealed that the synthetic CD-based multivalent ligands could efficiently inhibit Gal-3 binding to human airway epithelial cells, with an inhibitory capacity consistent with their binding affinity measured by SPR. The synthetic cyclodextrin-based ligands described in this study should be valuable for functional studies of human Gal-3 and potentially for therapeutic applications.
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