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.
Highlights
The galectin family of carbohydrate binding proteins have gained increasing interest as therapeutic targets in several diseases, such as chronic inflammation and cancer[1,2,3,4]
The results show striking differences in the cellular uptake of the inhibitors and of their intracellular potency, which correlates with their polar surface area (PSA)
We evaluated three previously published galectin-3 inhibitors for their cellular uptake and potency to inhibit galectin-3 in both the extra- and intracellular compartments
Summary
The galectin family of carbohydrate binding proteins have gained increasing interest as therapeutic targets in several diseases, such as chronic inflammation and cancer[1,2,3,4]. Apart from the extracellular activities of the galectin family, mediated through glycan binding, galectins play important roles in the intracellular compartments. We compared cell membrane permeability of three previously published high affinity galectin-3 inhibitors and compared their potency in inhibiting galectin-3 activities, in the cytosol and at the cell surface. The results show striking differences in the cellular uptake of the inhibitors and of their intracellular potency, which correlates with their polar surface area (PSA). These inhibitors may serve as useful tools in exploring the roles of galectin-3 in both cell and tissue cultures or in animal models and, importantly, may further our understanding of intracellular versus extracellular roles of galectin-3
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