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Exploring the Structural Space of the Galectin‐1–Ligand Interaction |
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| Authors: | Dr. Nadja Bertleff‐Zieschang Julian Bechold Dr. Clemens Grimm Dr. Michael Reutlinger Dr. Petra Schneider Prof. Dr. Gisbert Schneider Prof. Dr. Jürgen Seibel |
| Affiliation: | 1. Institute of Organic Chemistry, Julius Maximilians-Universit?t Würzburg, Würzburg, Germany;2. Biozentrum der Julius Maximilians-Universit?t Würzburg, Würzburg, Germany;3. Eidgen?ssische Technische Hochschule (ETH), Department Chemie und Angewandte Biowissenschaften, Zürich, Switzerland |
| 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. |
| Keywords: | carbohydrates fragment-based design ligand design stacking interactions X-ray diffraction |