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Structure-guided design of D-galactal derivatives with high affinity and selectivity for the galectin-8 N-terminal domain

DOI: 10.1021/acsmedchemlett.1c00371 DOI Help

Authors: Mujtaba Hassan (Lund University; University of Ljubljana) , Floriane Baussière (Lund University) , Samo Guzelj (University of Ljubljana) , Anders P. Sundin (Lund University) , Maria Håkansson (SARomics Biostructures AB) , Rebeka Kovačič (SARomics Biostructures AB) , Hakon Leffler (Lund University) , Tihomir Tomašič (University of Ljubljana) , Marko Anderluh (University of Ljubljana) , Žiga Jakopin (University of Ljubljana) , Ulf J. Nilsson (Lund University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 12 , PAGES 1745 - 1752

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 15916

Open Access Open Access

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.

Journal Keywords: Galectin-8N; d-galactal; benzimidazole; selectivity; X-ray crystallography; cytokine secretion

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 15/12/2021 08:26


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)