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Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids
[Image: see text] A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227030/ https://www.ncbi.nlm.nih.gov/pubmed/32134631 http://dx.doi.org/10.1021/acsinfecdis.0c00009 |
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author | Cervin, Jakob Boucher, Andrew Youn, Gyusaang Björklund, Per Wallenius, Ville Mottram, Lynda Sampson, Nicole S. Yrlid, Ulf |
author_facet | Cervin, Jakob Boucher, Andrew Youn, Gyusaang Björklund, Per Wallenius, Ville Mottram, Lynda Sampson, Nicole S. Yrlid, Ulf |
author_sort | Cervin, Jakob |
collection | PubMed |
description | [Image: see text] A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, the CT B subunit (CTB) has a noncanonical site that binds fucosylated structures, which in contrast to GM1 are highly expressed in the human intestine. Here we evaluate the capacity of norbornene polymers displaying galactose and/or fucose to block CTB binding to immobilized protein-linked glycan structures and also to primary human and murine small intestine epithelial cells (SI ECs). We show that the binding of CTB to human SI ECs is largely dependent on the noncanonical binding site, and interference with the canonical site has a limited effect while the opposite is observed with murine SI ECs. The galactose–fucose polymer blocks binding to fucosylated glycans but not to GM1. However, the preincubation of CT with the galactose–fucose polymer only partially blocks toxic effects on cultured human enteroid cells, while preincubation with GM1 completely blocks CT-mediated secretion. Our results support a model whereby the binding of fucose to the noncanonical site places CT in close proximity to scarcely expressed galactose receptors such as GM1 to enable binding via the canonical site leading to CT internalization and intoxication. Our finding also highlights the importance of complementing CTB binding studies with functional intoxication studies when assessing the efficacy inhibitors of CT. |
format | Online Article Text |
id | pubmed-7227030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-72270302020-05-18 Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids Cervin, Jakob Boucher, Andrew Youn, Gyusaang Björklund, Per Wallenius, Ville Mottram, Lynda Sampson, Nicole S. Yrlid, Ulf ACS Infect Dis [Image: see text] A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, the CT B subunit (CTB) has a noncanonical site that binds fucosylated structures, which in contrast to GM1 are highly expressed in the human intestine. Here we evaluate the capacity of norbornene polymers displaying galactose and/or fucose to block CTB binding to immobilized protein-linked glycan structures and also to primary human and murine small intestine epithelial cells (SI ECs). We show that the binding of CTB to human SI ECs is largely dependent on the noncanonical binding site, and interference with the canonical site has a limited effect while the opposite is observed with murine SI ECs. The galactose–fucose polymer blocks binding to fucosylated glycans but not to GM1. However, the preincubation of CT with the galactose–fucose polymer only partially blocks toxic effects on cultured human enteroid cells, while preincubation with GM1 completely blocks CT-mediated secretion. Our results support a model whereby the binding of fucose to the noncanonical site places CT in close proximity to scarcely expressed galactose receptors such as GM1 to enable binding via the canonical site leading to CT internalization and intoxication. Our finding also highlights the importance of complementing CTB binding studies with functional intoxication studies when assessing the efficacy inhibitors of CT. American Chemical Society 2020-03-05 2020-05-08 /pmc/articles/PMC7227030/ /pubmed/32134631 http://dx.doi.org/10.1021/acsinfecdis.0c00009 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Cervin, Jakob Boucher, Andrew Youn, Gyusaang Björklund, Per Wallenius, Ville Mottram, Lynda Sampson, Nicole S. Yrlid, Ulf Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids |
title | Fucose-Galactose
Polymers Inhibit Cholera Toxin Binding
to Fucosylated Structures and Galactose-Dependent Intoxication of
Human Enteroids |
title_full | Fucose-Galactose
Polymers Inhibit Cholera Toxin Binding
to Fucosylated Structures and Galactose-Dependent Intoxication of
Human Enteroids |
title_fullStr | Fucose-Galactose
Polymers Inhibit Cholera Toxin Binding
to Fucosylated Structures and Galactose-Dependent Intoxication of
Human Enteroids |
title_full_unstemmed | Fucose-Galactose
Polymers Inhibit Cholera Toxin Binding
to Fucosylated Structures and Galactose-Dependent Intoxication of
Human Enteroids |
title_short | Fucose-Galactose
Polymers Inhibit Cholera Toxin Binding
to Fucosylated Structures and Galactose-Dependent Intoxication of
Human Enteroids |
title_sort | fucose-galactose
polymers inhibit cholera toxin binding
to fucosylated structures and galactose-dependent intoxication of
human enteroids |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227030/ https://www.ncbi.nlm.nih.gov/pubmed/32134631 http://dx.doi.org/10.1021/acsinfecdis.0c00009 |
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