Exploring the Structural Space of the Galectin-1–Ligand Interaction

Abstract

Galectin-1 is a tumor-associated protein recognizing the Galβ1-4GlcNAc motif of cell-surface glycoconjugates. Herein, we report the stepwise expansion of a multifunctional natural scaffold based on N-acetyllactosamine (LacNAc). We obtained a LacNAc mimetic equipped with an alkynyl function on the 3′-hydroxy group of the disaccharide facing towards a binding pocket adjacent to the carbohydrate-recognition domain. It served as an anchor motif for further expansion by the Sharpless–Huisgen–Meldal reaction, which resulted in ligands with a binding mode almost identical to that of the natural carbohydrate template. X-ray crystallography provided a structural understanding of the galectin-1–ligand interactions. The results of this study enable the development of bespoke ligands for members of the galectin target family.