3 years ago

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

Exploring the Structural Space of the Galectin-1–Ligand Interaction
Jürgen Seibel, Petra Schneider, Nadja Bertleff-Zieschang, Michael Reutlinger, Clemens Grimm, Gisbert Schneider, Julian Bechold
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. In a bind: Expansion of the natural N-acetyllactosamine (LacNAc) binding scaffold by a synthetic multifunctional LacNAc mimetic leads to expanded ligands that share a binding mode that is almost identical to that of the natural carbohydrate template. X-ray crystallography provides a structural understanding of the galectin-1–ligand interactions. The results of this study enable the development of ligands for members of the galectin target family.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cbic.201700251

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