Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment

Abstract Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) an...

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Autores principales:	Ciaran A. Shaughnessy, Pamela L. Zeitlin, Preston E. Bratcher
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ada0900b04f2474491bb981f326adf27
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spelling	oai:doaj.org-article:ada0900b04f2474491bb981f326adf272021-12-02T17:13:22ZElexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment10.1038/s41598-021-99184-12045-2322https://doaj.org/article/ada0900b04f2474491bb981f326adf272021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99184-1https://doaj.org/toc/2045-2322Abstract Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.Ciaran A. ShaughnessyPamela L. ZeitlinPreston E. BratcherNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ciaran A. Shaughnessy Pamela L. Zeitlin Preston E. Bratcher Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment
description	Abstract Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.
format	article
author	Ciaran A. Shaughnessy Pamela L. Zeitlin Preston E. Bratcher
author_facet	Ciaran A. Shaughnessy Pamela L. Zeitlin Preston E. Bratcher
author_sort	Ciaran A. Shaughnessy
title	Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment
title_short	Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment
title_full	Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment
title_fullStr	Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment
title_full_unstemmed	Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment
title_sort	elexacaftor is a cftr potentiator and acts synergistically with ivacaftor during acute and chronic treatment
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ada0900b04f2474491bb981f326adf27
work_keys_str_mv	AT ciaranashaughnessy elexacaftorisacftrpotentiatorandactssynergisticallywithivacaftorduringacuteandchronictreatment AT pamelalzeitlin elexacaftorisacftrpotentiatorandactssynergisticallywithivacaftorduringacuteandchronictreatment AT prestonebratcher elexacaftorisacftrpotentiatorandactssynergisticallywithivacaftorduringacuteandchronictreatment
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Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment

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