VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level

Guiying Cui; Brandon B. Stauffer; Barry R. Imhoff; Andras Rab; Jeong S. Hong; Eric J. Sorscher; Nael A. McCarty

doi:10.1038/s41598-019-49921-4

VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level

Guiying Cui, Brandon B. Stauffer, Barry R. Imhoff, Andras Rab, Jeong S. Hong, Eric J. Sorscher, Nael A. McCarty

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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.

Original language	English
Article number	13460
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-49921-4
State	Published - 1 Dec 2019
Externally published	Yes

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title = "VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level",

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.",

author = "Guiying Cui and Stauffer, {Brandon B.} and Imhoff, {Barry R.} and Andras Rab and Hong, {Jeong S.} and Sorscher, {Eric J.} and McCarty, {Nael A.}",

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T1 - VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level

AU - Cui, Guiying

AU - Stauffer, Brandon B.

AU - Imhoff, Barry R.

AU - Rab, Andras

AU - Hong, Jeong S.

AU - Sorscher, Eric J.

AU - McCarty, Nael A.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level

Abstract

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