VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level.
Sci Rep
; 9(1): 13460, 2019 09 17.
Article
em En
| MEDLINE
| ID: mdl-31530897
ABSTRACT
VX-770 (ivacaftor) is approved for clinical use in CF patients bearing multiple CFTR mutations. VX-770 potentiated wildtype CFTR and several disease mutants expressed in oocytes in a manner modulated by PKA-mediated phosphorylation. Potentiation of some other mutants, including G551D-CFTR, was less dependent upon the level of phosphorylation, likely related to the severe gating defects in these mutants exhibited in part by a shift in PKA sensitivity to activation, possibly due to an electrostatic interaction of D551 with K1250. Phosphorylation-dependent potentiation of wildtype CFTR and other variants also was observed in epithelial cells. Hence, the efficacy of potentiators may be obscured by a ceiling effect when drug screening is performed under strongly phosphorylating conditions. These results should be considered in campaigns for CFTR potentiator discovery, and may enable the expansion of VX-770 to CF patients bearing ultra-orphan CFTR mutations.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinolonas
/
Regulador de Condutância Transmembrana em Fibrose Cística
/
Aminofenóis
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article