Benzimidazole-galactosides bind selectively to the galectin-8 N-terminal domainHassan, Mujtaba (Avtor) van Klaveren, Sjors (Avtor) Håkansson, Maria (Avtor) Diehl, Carl (Avtor) Kovačič, Rebeka (Avtor) Baussière, Floriane (Avtor) Sundin, Anders (Avtor) Dernovšek, Jaka (Avtor) Anderluh, Marko (Avtor) Tomašič, Tihomir (Avtor) Jakopin, Žiga (Avtor) benzimidazolegalectin-8Nquinolineselectivitymolecular dynamicsx-ray crystallographyWe 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 1.6Å. 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%[micro]M 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-8.20212022-09-30 09:12:51Članek v reviji141507sl