VX-770-mediated Potentiation of Numerous Human CFTR Disease Mutants is Influenced by Phosphorylation Level

Overview

Journal Sci Rep

Specialty Science

Date 2019 Sep 19

PMID 31530897

Citations 22

Authors

Guiying Cui

Brandon B Stauffer

Barry R Imhoff

Andras Rab

Jeong S Hong

Eric J Sorscher

Nael A McCarty

Affiliations

Soon will be listed here.

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.

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