2. Academic Validation
  3. Benzimidazole-galactosides bind selectively to the Galectin-8 N-Terminal domain: Structure-based design and optimisation

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

  • Eur J Med Chem. 2021 Nov 5;223:113664. doi: 10.1016/j.ejmech.2021.113664.
Mujtaba Hassan 1,  Sjors van Klaveren 1,  Maria Håkansson 2,  Carl Diehl 2,  Rebeka Kovačič 2,  Floriane Baussière 3,  Anders P Sundin 3,  Jaka Dernovšek 4,  Björn Walse 2,  Fredrik Zetterberg 5,  Hakon Leffler 6,  Marko Anderluh 4,  Tihomir Tomašič 4,  Žiga Jakopin 4,  Ulf J Nilsson 7
Affiliations

Affiliations

  • 1 Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
  • 2 SARomics Biostructures AB, Medicon Village, SE-223 81, Lund, Sweden.
  • 3 Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden.
  • 4 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
  • 5 Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46, Gothenburg, Sweden.
  • 6 Department of Laboratory Medicine, Section MIG, Lund University BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
  • 7 Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden. Electronic address: ulf.nilsson@chem.lu.se.
PMID: 34225180 DOI: 10.1016/j.ejmech.2021.113664
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.

Keywords

Benzimidazole; Galectin-8N; Molecular dynamics; Quinoline; Selectivity; X-ray crystallography.

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