Extracellular and intracellular small-molecule galectin-3 inhibitors

John Stegmayr; Fredrik Zetterberg; Michael C. Carlsson; Xiaoli Huang; Gunjan Sharma; Barbro Kahl-Knutson; Hans Schambye; Ulf J. Nilsson; Stina Oredsson; Hakon Leffler

doi:10.1038/s41598-019-38497-8

Extracellular and intracellular small-molecule galectin-3 inhibitors

John Stegmayr^*, Fredrik Zetterberg, Michael C. Carlsson, Xiaoli Huang, Gunjan Sharma, Barbro Kahl-Knutson, Hans Schambye, Ulf J. Nilsson, Stina Oredsson, Hakon Leffler

^*Corresponding author for this work

Glycomics Program

23 Citations (Scopus)

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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.

Original language	English
Article number	2186
Journal	Scientific Reports
Volume	9
Issue number	1
Number of pages	12
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-019-38497-8
Publication status	Published - 2019

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Extracellular and intracellular small-molecule galectin-3 inhibitorsFinal published version, 4.33 MBLicence: CC BY

Cite this

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title = "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.",

author = "John Stegmayr and Fredrik Zetterberg and Carlsson, {Michael C.} and Xiaoli Huang and Gunjan Sharma and Barbro Kahl-Knutson and Hans Schambye and Nilsson, {Ulf J.} and Stina Oredsson and Hakon Leffler",

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AU - Stegmayr, John

AU - Zetterberg, Fredrik

AU - Carlsson, Michael C.

AU - Huang, Xiaoli

AU - Sharma, Gunjan

AU - Kahl-Knutson, Barbro

AU - Schambye, Hans

AU - Nilsson, Ulf J.

AU - Oredsson, Stina

AU - Leffler, Hakon

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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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DO - 10.1038/s41598-019-38497-8

M3 - Journal article

C2 - 30778105

AN - SCOPUS:85061733012

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 2186

ER -

Extracellular and intracellular small-molecule galectin-3 inhibitors

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