Benzimidazole–galactosides bind selectively to the Galectin-8 N-Terminal domain: Structure-based design and optimisation

Hassan, Mujtaba; Klaveren, Sjors van; Håkansson, Maria; Diehl, Carl; Kovacic, R.; Baussière, Floriane; Sundin, Anders; Dernovšek, Jaka; Walse, Björn; Zetterberg, Fredrik; Leffler, Hakon; Anderluh, Marko; Tomašič, Tihomir; Nilsson, Ulf J.

doi:10.1016/j.ejmech.2021.113664

Cited by 15 publications

(23 citation statements)

References 42 publications

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“…To investigate the binding modes of compounds 6a and 9 for galectin-8N, we solved their X-ray crystal structures in complex with galectin-8N according to the previously published protocol. 20 Galectin-8N was first cocrystallized with lactose, and then the ligands were soaked into galectin-8N-lactose crystals, followed by collection of X-ray diffraction data at 1.52 and 2.1 Å resolution for the galectin-8N– 6a complex and galectin-8N– 9 complex, respectively. Both complexes showed that the O4 and O6 of the d -galactal portion bind to galectin-8N in a similar manner as the corresponding oxygens in the d -galactosides.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Achieving selectivity for galectin-8N over the other mammalian galectins has always been a challenging task, due to the substantial similarity of different galectin CRDs and even between 8N and 8C CRDs. The previously reported synthetic galectin-8N ligands include a coumarin-galactoside derivative ( K d = 200 μM), a methyl β- d -galactomalonyl phenyl ester ( K d = 5.7 μM), a quinoline-galactoside ( K d = 1.5 μM), and a recently reported benzimidazole-galactoside 1 ( K d = 1.8 μM) (Figure ). Of particular note is a recently reported tricyclic galactose-benzene hybrid 2 ( K d = 180 μM) which has about 2-fold selectivity over galectin-1 and a high 23-fold selectivity over galectin-3 (Figure ).…”

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confidence: 99%

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Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

Hassan

Baussière

Guzelj

et al. 2021

ACS Med. Chem. Lett.

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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 K d 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-(4sulfophenyl)-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.

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Section: Results and Discussionmentioning

confidence: 99%

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confidence: 99%

Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

Hassan

Baussière

Guzelj

et al. 2021

ACS Med. Chem. Lett.

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“…They behave independently in the full length protein and the addition of a ligand specific for one CRD does not affect the binding to the other [19,20] . Yet, both galectin‐8 CRDs are required for its function so that blocking of either will hamper the functionality of the whole protein [21,22] . The N‐terminal CRD has an enhanced binding to structures containing 3‐ O ‐sialylated galactose, unique among galectins, and the crystal structure with such a preferred ligand, the trisaccharide 3‐SiaLac, has been solved (Figure 1A) [23] .…”

Section: Introductionmentioning

confidence: 99%

Selective Monovalent Galectin‐8 Ligands Based on 3‐Lactoylgalactoside

et al. 2021

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Galectin‐8 has gained attention as a potential new pharmacological target for the treatment of various diseases, including cancer, inflammation, and disorders associated with bone mass reduction. To that end, new molecular probes are needed in order to better understand its role and its functions. Herein we aimed to improve the affinity and target selectivity of a recently published galectin‐8 ligand, 3‐O‐[1‐carboxyethyl]‐β‐d‐galactopyranoside, by introducing modifications at positions 1 and 3 of the galactose. Affinity data measured by fluorescence polarization show that the most potent compound reached a KD of 12 μM. Furthermore, reasonable selectivity versus other galectins was achieved, making the highlighted compound a promising lead for the development of new selective and potent ligands for galectin‐8 as molecular probes to examine the protein's role in cell‐based and in vivo studies.

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“…[6] Following non-classical secretion, [7] carbohydrate recognition and protein-protein interactions modulate cell growth, death, and adhesion to influence lymphangiogenesis, tumour survival and metastasis. [8][9][10][11] Furthermore, galectin-8, in association with anti-galectin-8 antibodies, [12,13] is implicated in rheumatoid arthritis and is a protective factor for inflammatory damage to the central nervous system. [14] The galectin family derives its name from the fact that they are lectins (sugar-binding proteins) with specificity for βgalactoside carbohydrates.…”

Section: Introductionmentioning

confidence: 99%

“…However, it is a nearly equipotent ligand for galectin-3. [11] Recently, d-galactal analogue 2 was discovered, [22] in which the galactal moiety confers selectivity on galectin binding, but at the cost of affinity. The discovery of a selective tricyclic galactalbenzene hybrid 3 has been described, which has an affinity of 180 μM for galectin-8N.…”

Section: Introductionmentioning

confidence: 99%

Selective Galectin‐8N Ligands: The Design and Synthesis of Phthalazinone‐d‐Galactals

et al. 2021

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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.

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Benzimidazole–galactosides bind selectively to the Galectin-8 N-Terminal domain: Structure-based design and optimisation

Cited by 15 publications

References 42 publications

Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

Selective Monovalent Galectin‐8 Ligands Based on 3‐Lactoylgalactoside

Selective Galectin‐8N Ligands: The Design and Synthesis of Phthalazinone‐d‐Galactals

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