Selective Galectin-8N Ligands: The Design and Synthesis of Phthalazinone-d-Galactals
Sjors van Klaveren
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Faculty of Science, Naturvetarvägen 14, 223 62 Lund, Sweden
Search for more papers by this authorDr. Anders P. Sundin
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Faculty of Science, Naturvetarvägen 14, 223 62 Lund, Sweden
Search for more papers by this authorProf. Žiga Jakopin
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Search for more papers by this authorProf. Marko Anderluh
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Search for more papers by this authorProf. Hakon Leffler
Department of Laboratory Medicine, Section MIG, Lund University, BMC−C1228b, Klinikgatan 28, 221 84 Lund, Sweden
Search for more papers by this authorCorresponding Author
Prof. Ulf J. Nilsson
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Faculty of Science, Naturvetarvägen 14, 223 62 Lund, Sweden
Search for more papers by this authorCorresponding Author
Prof. Tihomir Tomašič
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Search for more papers by this authorSjors van Klaveren
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Faculty of Science, Naturvetarvägen 14, 223 62 Lund, Sweden
Search for more papers by this authorDr. Anders P. Sundin
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Faculty of Science, Naturvetarvägen 14, 223 62 Lund, Sweden
Search for more papers by this authorProf. Žiga Jakopin
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Search for more papers by this authorProf. Marko Anderluh
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Search for more papers by this authorProf. Hakon Leffler
Department of Laboratory Medicine, Section MIG, Lund University, BMC−C1228b, Klinikgatan 28, 221 84 Lund, Sweden
Search for more papers by this authorCorresponding Author
Prof. Ulf J. Nilsson
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Faculty of Science, Naturvetarvägen 14, 223 62 Lund, Sweden
Search for more papers by this authorCorresponding Author
Prof. Tihomir Tomašič
Chair of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Search for more papers by this authorGraphical Abstract
Our novel galectin-8N ligands show an impressive 10-fold selectivity over other human galectins. The two discovered binding poses of the galactal-phthalazinone ligand were analysed using molecular dynamics simulations and metadynamics analysis. These selective ligands may help dissect the function of carbohydrate recognition of galectin-8 in its numerous roles, including the immune response and tumour-related lymphangiogenesis.
Abstract
Ligand selectivity among the highly conserved galectins has been an ever-challenging objective. For galectin-8, a protein prevalent in both pathology and tissue distribution, we report phthalazinone-galactals that show excellent selectivity for the galectin-8N-terminal domain. A dissection of structure–activity relationships of the phthalazinone and an extensive molecular dynamics meta-analysis accompany the discovery of the selective galectin-8N ligands presented here. These selective compounds will facilitate the study of galectin-8 biology and may have pharmaceutical relevance in the wide range of galectin-8 associated pathologies.
Conflict of interest
H.L. and U.J.N. are shareholders in Galecto Biotech AB, a company developing galectin inhibitors. The other authors have no conflicts to declare
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