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
  • 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: [email protected].
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.
Products