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A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae

Vibrio cholerae uses cholera toxin (CT) to cause cholera, a severe diarrheal disease in humans that can lead to death within hours of the onset of symptoms. The catalytic activity of CT in target epithelial cells increases cellular levels of 3′,5′-cyclic AMP (cAMP), leading to the activation of the...

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Autores principales: Rivera-Chávez, Fabian, Meader, Bradley T., Akosman, Sinan, Koprivica, Vuk, Mekalanos, John J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948642/
https://www.ncbi.nlm.nih.gov/pubmed/35324722
http://dx.doi.org/10.3390/toxins14030225
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author Rivera-Chávez, Fabian
Meader, Bradley T.
Akosman, Sinan
Koprivica, Vuk
Mekalanos, John J.
author_facet Rivera-Chávez, Fabian
Meader, Bradley T.
Akosman, Sinan
Koprivica, Vuk
Mekalanos, John J.
author_sort Rivera-Chávez, Fabian
collection PubMed
description Vibrio cholerae uses cholera toxin (CT) to cause cholera, a severe diarrheal disease in humans that can lead to death within hours of the onset of symptoms. The catalytic activity of CT in target epithelial cells increases cellular levels of 3′,5′-cyclic AMP (cAMP), leading to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR), an apical ion channel that transports chloride out of epithelial cells, resulting in an electrolyte imbalance in the intestinal lumen and massive water loss. Here we report that when administered perorally, benzopyrimido-pyrrolo-oxazinedione, (R)-BPO-27), a potent small molecule inhibitor of CFTR, blocked disease symptoms in a mouse model for acute diarrhea caused by toxigenic V. cholerae. We show that both (R)-BPO-27 and its racemic mixture, (R/S)-BPO-27, are able to protect mice from CT-dependent diarrheal disease and death. Furthermore, we show that, consistent with the ability of the compound to block the secretory diarrhea induced by CT, BPO-27 has a measurable effect on suppressing the gut replication and survival of V. cholerae, including a 2010 isolate from Haiti that is representative of the most predominant ‘variant strains’ that are causing epidemic and pandemic cholera worldwide. Our results suggest that BPO-27 should advance to human Phase I studies that could further address its safety and efficacy as therapeutic or preventative drug intervention for diarrheal syndromes, including cholera, that are mediated by CFTR channel activation.
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spelling pubmed-89486422022-03-26 A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae Rivera-Chávez, Fabian Meader, Bradley T. Akosman, Sinan Koprivica, Vuk Mekalanos, John J. Toxins (Basel) Article Vibrio cholerae uses cholera toxin (CT) to cause cholera, a severe diarrheal disease in humans that can lead to death within hours of the onset of symptoms. The catalytic activity of CT in target epithelial cells increases cellular levels of 3′,5′-cyclic AMP (cAMP), leading to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR), an apical ion channel that transports chloride out of epithelial cells, resulting in an electrolyte imbalance in the intestinal lumen and massive water loss. Here we report that when administered perorally, benzopyrimido-pyrrolo-oxazinedione, (R)-BPO-27), a potent small molecule inhibitor of CFTR, blocked disease symptoms in a mouse model for acute diarrhea caused by toxigenic V. cholerae. We show that both (R)-BPO-27 and its racemic mixture, (R/S)-BPO-27, are able to protect mice from CT-dependent diarrheal disease and death. Furthermore, we show that, consistent with the ability of the compound to block the secretory diarrhea induced by CT, BPO-27 has a measurable effect on suppressing the gut replication and survival of V. cholerae, including a 2010 isolate from Haiti that is representative of the most predominant ‘variant strains’ that are causing epidemic and pandemic cholera worldwide. Our results suggest that BPO-27 should advance to human Phase I studies that could further address its safety and efficacy as therapeutic or preventative drug intervention for diarrheal syndromes, including cholera, that are mediated by CFTR channel activation. MDPI 2022-03-18 /pmc/articles/PMC8948642/ /pubmed/35324722 http://dx.doi.org/10.3390/toxins14030225 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rivera-Chávez, Fabian
Meader, Bradley T.
Akosman, Sinan
Koprivica, Vuk
Mekalanos, John J.
A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae
title A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae
title_full A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae
title_fullStr A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae
title_full_unstemmed A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae
title_short A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae
title_sort potent inhibitor of the cystic fibrosis transmembrane conductance regulator blocks disease and morbidity due to toxigenic vibrio cholerae
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948642/
https://www.ncbi.nlm.nih.gov/pubmed/35324722
http://dx.doi.org/10.3390/toxins14030225
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