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Extracellular and intracellular small-molecule galectin-3 inhibitors

Stegmayr, John LU ; Zetterberg, Fredrik; Carlsson, Michael C. LU ; Huang, Xiaoli LU ; Sharma, Gunjan LU ; Kahl-Knutson, Barbro LU ; Schambye, Hans; Nilsson, Ulf J. LU ; Oredsson, Stina LU and Leffler, Hakon LU (2019) In Scientific Reports 9(1).
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
9
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85061733012
ISSN
2045-2322
DOI
10.1038/s41598-019-38497-8
language
English
LU publication?
yes
id
2d4761ab-2ec6-47d8-808a-f8300d5fbd6b
date added to LUP
2019-02-25 10:13:39
date last changed
2019-03-27 04:39:17
@article{2d4761ab-2ec6-47d8-808a-f8300d5fbd6b,
  abstract     = {<p>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.</p>},
  articleno    = {2186},
  author       = {Stegmayr, John and Zetterberg, Fredrik and Carlsson, Michael C. and Huang, Xiaoli and Sharma, Gunjan and Kahl-Knutson, Barbro and Schambye, Hans and Nilsson, Ulf J. and Oredsson, Stina and Leffler, Hakon},
  issn         = {2045-2322},
  language     = {eng},
  month        = {02},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Extracellular and intracellular small-molecule galectin-3 inhibitors},
  url          = {http://dx.doi.org/10.1038/s41598-019-38497-8},
  volume       = {9},
  year         = {2019},
}