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

Hassan, Mujtaba (author), Baussière, Floriane (author), Guzelj, Samo (author), Sundin, Anders (author), Håkansson, Maria (author), Kovačič, Rebeka (author), Leffler, Hakon (author), Tomašič, Tihomir (author), Anderluh, Marko (author), Jakopin, Žiga (author)

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.

• Language: English
• Keywords: Galectin-8N, d-galactal, benzimidazole, selectivity, X-ray crystallography, cytokine secretion
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: Str. 1745-1752
• Numbering: Vol. 12, iss. 11
• PID: 20.500.12556/RUL-141454
• UDC: 615.4:54:616-006
• ISSN on article: 1948-5875
• DOI: 10.1021/acsmedchemlett.1c00371
• COBISS.SI-ID: 83202819
• Publication date in RUL: 29.09.2022

Record is a part of a journal

• Title: ACS medicinal chemistry letters
• Publisher: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Projects

• Funder: Other - Other funder or multiple funders
• Funding programme: Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement
• Project number: 765581