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Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands

Author:
  • Kristoffer Peterson
  • Patrick M. Collins
  • Xiaoli Huang
  • Barbro Kahl-Knutsson
  • Sofia Essén
  • Fredrik R. Zetterberg
  • Stina Oredsson
  • Hakon Leffler
  • Helen Blanchard
  • Ulf J. Nilsson
Publishing year: 2018
Language: English
Pages: 24913-24922
Publication/Series: RSC Advances
Volume: 8
Issue: 44
Document type: Journal article
Publisher: Royal Society of Chemistry

Abstract english

A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3′ substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were studied with X-ray crystallography. One of the thiophene moieties was positioned deeper into the pocket than previously reported phenyltriazoles and formed close contacts with Val31, Ser29, Gly124, and Asp123. The affinity and structural analysis thus revealed that steric and electronic optimization of five-membered aromatic heterocycle binding in a narrow galectin-1 subsite confers high affinity and selectivity.

Keywords

  • Biochemistry and Molecular Biology

Other

Published
  • ISSN: 2046-2069
Stina Oredsson
E-mail: stina [dot] oredsson [at] biol [dot] lu [dot] se

Professor

Functional zoology

+46 46 222 94 97

B-C208

4

Principal investigator

LUCC - Lund University Cancer Centre

Research group

Animal Physiology

Projects

Cell proliferation

Doctoral students and postdocs

PhD Students, main supervisor

Wendy Soria Sotillo

PhD Students, assistant supervisor

Atena Malakpour Permlid