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Galectin Inhibitors – Molecular Tools in Biomedical Research and Clinical Implications

Stegmayr, John LU (2017)
Abstract
Galectins are β-galactoside-binding lectins, which are present in both the intracellular and extracellular environments of cells. During the last two decades, galectins have gained increasing interest as drug targets in various diseases, such as chronic inflammation (fibrosis) and cancer, in which galectins have been shown to play important, and sometimes rate-limiting, roles. Galectins have e.g. been implicated in cell-cell/matrix interactions, apoptosis, cell proliferation, cell migration, protein trafficking, and several immune modulatory functions. Because of this, development of galectin inhibitors has been of great importance, both as research tools to deepen our understanding of galectins in biological environments and as possible... (More)
Galectins are β-galactoside-binding lectins, which are present in both the intracellular and extracellular environments of cells. During the last two decades, galectins have gained increasing interest as drug targets in various diseases, such as chronic inflammation (fibrosis) and cancer, in which galectins have been shown to play important, and sometimes rate-limiting, roles. Galectins have e.g. been implicated in cell-cell/matrix interactions, apoptosis, cell proliferation, cell migration, protein trafficking, and several immune modulatory functions. Because of this, development of galectin inhibitors has been of great importance, both as research tools to deepen our understanding of galectins in biological environments and as possible pharmaceuticals. In this thesis, two classes of galectin inhibitors are evaluated for these purposes, namely synthetic small-molecule galectin inhibitors and a heterogeneous group of plant-derived polysaccharides.
The former inhibitor class has during the last decades been well-characterized for galectin inhibition in several biochemical in vitro assays, but are less investigated for biological activity (especially on a cellular level). To address this, we designed a novel assay for measurement of intracellular activity of galectin inhibitors, based on the phenomenon that galectins accumulate around disrupted vesicles. Furthermore, we show that it is possible to synthesize high-affinity galectin inhibitors with significant differences in cellular uptake, which thus may become valuable tools in the investigation of intracellular versus extracellular function of galectins. In another translational study of idiopathic pulmonary fibrosis, utilizing a bleomycin-induced lung fibrosis model in mice, we additionally show that one synthetic small-molecule galectin inhibitor may have clinical use in this disease.
The plant-derived polysaccharide class of inhibitors has shown various biological activities and anti-cancer properties in cell cultures and in vivo. The mechanisms of these activities have, in a multitude of studies, been attributed to inhibition of galectins, mainly galectin-3, but proper biochemical analysis supporting this is missing. In this thesis, we show that this class of polysaccharides, in fact, is a very pore group of galectin inhibitors or in most cases does not inhibit the galectins at all.
In conclusion, the work presented in this thesis will hopefully guide the development of future galectin inhibitors, to be used as molecular tools in galectin-related research and as potential therapeutics in the clinic.
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author
supervisor
opponent
  • professor Griffioen, Arjan W., University Medical Center Amsterdam
organization
publishing date
type
Thesis
publication status
published
subject
keywords
galectins, inhibitors, evaluation assays, cell culture, idiopathic pulmonary fibrosis, synthetic small-molecule galectin inhibitors, plant-derived polysaccharides
pages
96 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund.
defense date
2017-01-13 13:00
ISBN
9789176193853
language
English
LU publication?
yes
id
22964b32-cec3-41e9-b72a-256409448c2a
date added to LUP
2016-12-21 13:42:04
date last changed
2016-12-28 18:28:55
@phdthesis{22964b32-cec3-41e9-b72a-256409448c2a,
  abstract     = {Galectins are β-galactoside-binding lectins, which are present in both the intracellular and extracellular environments of cells. During the last two decades, galectins have gained increasing interest as drug targets in various diseases, such as chronic inflammation (fibrosis) and cancer, in which galectins have been shown to play important, and sometimes rate-limiting, roles. Galectins have e.g. been implicated in cell-cell/matrix interactions, apoptosis, cell proliferation, cell migration, protein trafficking, and several immune modulatory functions. Because of this, development of galectin inhibitors has been of great importance, both as research tools to deepen our understanding of galectins in biological environments and as possible pharmaceuticals. In this thesis, two classes of galectin inhibitors are evaluated for these purposes, namely synthetic small-molecule galectin inhibitors and a heterogeneous group of plant-derived polysaccharides.<br/>The former inhibitor class has during the last decades been well-characterized for galectin inhibition in several biochemical in vitro assays, but are less investigated for biological activity (especially on a cellular level). To address this, we designed a novel assay for measurement of intracellular activity of galectin inhibitors, based on the phenomenon that galectins accumulate around disrupted vesicles. Furthermore, we show that it is possible to synthesize high-affinity galectin inhibitors with significant differences in cellular uptake, which thus may become valuable tools in the investigation of intracellular versus extracellular function of galectins. In another translational study of idiopathic pulmonary fibrosis, utilizing a bleomycin-induced lung fibrosis model in mice, we additionally show that one synthetic small-molecule galectin inhibitor may have clinical use in this disease.<br/>The plant-derived polysaccharide class of inhibitors has shown various biological activities and anti-cancer properties in cell cultures and in vivo. The mechanisms of these activities have, in a multitude of studies, been attributed to inhibition of galectins, mainly galectin-3, but proper biochemical analysis supporting this is missing. In this thesis, we show that this class of polysaccharides, in fact, is a very pore group of galectin inhibitors or in most cases does not inhibit the galectins at all.<br/>In conclusion, the work presented in this thesis will hopefully guide the development of future galectin inhibitors, to be used as molecular tools in galectin-related research and as potential therapeutics in the clinic.<br/>},
  author       = {Stegmayr, John},
  isbn         = {9789176193853},
  keyword      = {galectins,inhibitors,evaluation assays,cell culture,idiopathic pulmonary fibrosis,synthetic small-molecule galectin inhibitors,plant-derived polysaccharides},
  language     = {eng},
  pages        = {96},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Galectin Inhibitors – Molecular Tools in Biomedical Research and Clinical Implications},
  year         = {2017},
}