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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	Structure-guided design of D-galactal derivatives with high affinity and selectivity for the galectin-8 N-terminal domain Mujtaba Hassan , Floriane Baussière , Samo Guzelj , Anders P. Sundin , Maria Håkansson , Rebeka Kovačič , Hakon Leffler , Tihomir Tomašič , Marko Anderluh , Žiga Jakopin , Ulf J. Nilsson Acs Medicinal Chemistry Letters 12, 1745 - 1752 DOI: 10.1021/acsmedchemlett.1c00371 Diamond Proposal Number(s): [15916] Open Access Show Abstract ▼ Abstract: Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a Kd of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents.	Nov 2021
I04-Macromolecular Crystallography	Benzimidazole–galactosides bind selectively to the Galectin-8 N-Terminal domain: Structure-based design and optimisation Mujtaba Hassan , Sjors Van Klaveren , Maria Håkansson , Carl Diehl , Rebeka Kovačič , Floriane Baussière , Anders Sundin , Jaka Dernovšek , Björn Walse , Fredrik Zetterberg , Hakon Leffler , Marko Anderluh , Tihomir Tomašič , Žiga Jakopin , Ulf J. Nilsson European Journal Of Medicinal Chemistry 19 DOI: 10.1016/j.ejmech.2021.113664 Diamond Proposal Number(s): [23282] Show Abstract ▼ Abstract: We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)–galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.	Jun 2021

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