Extracellular and intracellular small-molecule galectin-3 inhibitors.

Abstract

Galectin-3 is a carbohydrate binding protein which has important roles in cancer and immunity. Potent galectin-3 inhibitors have been synthesized, for experimental purposes and potential clinical use. As galectin-3 is implicated in both intra- and extracellular activities, permeability of galectin-3 inhibitors is an important parameter determining biological effects. We compared the cellular uptake of galectin-3 inhibitors and their potency in the intracellular or extracellular space. The inhibitors differed in their polar surface area (PSA), but had similar affinities for galectin-3. Using a well-established permeability assay, we confirmed that the uptake was significantly higher for the inhibitor with the lowest PSA, as expected. To analyze intracellular activity of the inhibitors, we developed a novel assay based on galectin-3 accumulation around damaged intracellular vesicles. The results show striking differences between the inhibitors intracellular potency, correlating with their PSAs. To test extracellular activity of the inhibitors, we analyzed their potency to block binding of galectin-3 to cell surfaces. All inhibitors were equally able to block galectin-3 binding to cells and this was proportional to their affinity for galectin-3. These inhibitors may serve as useful tools in exploring biological roles of galectin-3 and may further our understanding of intracellular versus extracellular roles of galectin-3.

• Authors: John Stegmayr, Fredrik Zetterberg, Michael C Carlsson, Xiaoli Huang, Gunjan Sharma, Barbro Kahl-Knutson, Hans Schambye, Ulf J Nilsson, Stina Oredsson, Hakon Leffler
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 2186 (02 18 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 30778105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Proteins
• Galactosides
• Galectin 3
• Galectins
• LGALS3 protein, human
• Thiogalactosides

Topics

• Animals
• Binding Sites
• Blood Proteins
• Breast Neoplasms (drug therapy, metabolism, pathology)
• CHO Cells
• Caco-2 Cells
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Cell Membrane Permeability
• Cell Proliferation (drug effects)
• Cricetulus
• Drug Evaluation, Preclinical
• Female
• Galactosides (chemistry, pharmacokinetics, pharmacology)
• Galectin 3 (antagonists & inhibitors, chemistry, genetics)
• Galectins
• Humans
• MCF-7 Cells
• Molecular Structure
• Thiogalactosides (chemistry, pharmacokinetics, pharmacology)