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.
CITATION STYLE
Cui, G., Stauffer, B. B., Imhoff, B. R., Rab, A., Hong, J. S., Sorscher, E. J., & McCarty, N. A. (2019). VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-49921-4
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