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The Epithelial Sodium Channel—An Underestimated Drug Target

Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorder...

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Autores principales: Lemmens-Gruber, Rosa, Tzotzos, Susan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178586/
https://www.ncbi.nlm.nih.gov/pubmed/37175488
http://dx.doi.org/10.3390/ijms24097775
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author Lemmens-Gruber, Rosa
Tzotzos, Susan
author_facet Lemmens-Gruber, Rosa
Tzotzos, Susan
author_sort Lemmens-Gruber, Rosa
collection PubMed
description Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.
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spelling pubmed-101785862023-05-13 The Epithelial Sodium Channel—An Underestimated Drug Target Lemmens-Gruber, Rosa Tzotzos, Susan Int J Mol Sci Review Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents. MDPI 2023-04-24 /pmc/articles/PMC10178586/ /pubmed/37175488 http://dx.doi.org/10.3390/ijms24097775 Text en © 2023 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 Review
Lemmens-Gruber, Rosa
Tzotzos, Susan
The Epithelial Sodium Channel—An Underestimated Drug Target
title The Epithelial Sodium Channel—An Underestimated Drug Target
title_full The Epithelial Sodium Channel—An Underestimated Drug Target
title_fullStr The Epithelial Sodium Channel—An Underestimated Drug Target
title_full_unstemmed The Epithelial Sodium Channel—An Underestimated Drug Target
title_short The Epithelial Sodium Channel—An Underestimated Drug Target
title_sort epithelial sodium channel—an underestimated drug target
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178586/
https://www.ncbi.nlm.nih.gov/pubmed/37175488
http://dx.doi.org/10.3390/ijms24097775
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