Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR.
J Cyst Fibros
; 20(5): 895-898, 2021 09.
Article
em En
| MEDLINE
| ID: mdl-33775603
ABSTRACT
Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Piridinas
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Pirrolidinas
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Regulador de Condutância Transmembrana em Fibrose Cística
/
Fibrose Cística
Limite:
Humans
Idioma:
En
Revista:
J Cyst Fibros
Ano de publicação:
2021
Tipo de documento:
Article