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Author Notes:

Nael A. McCarty, Email: namccar@emory.edu

G.C., B.B.S. and N.A.M. participated in research design; G.C., B.B.S., B.R.I., A.R. and J.S.H. conducted experiments; G.C. and B.B.S. analyzed data; G.C., B.B.S. and N.A.M. wrote or contributed to the editing of the manuscript; G.C., B.B.S., E.J.S. and N.A.M. approved final version of manuscript.

The authors declare no competing interests.

Subject:

Research Funding:

This work was supported by National Institutes of Health [Grants DK-056481, DK-075016]; the Cystic Fibrosis Foundation [CFF MCCART14GO] and an Emory/Children’s EECRC 2015 seed grant.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • TRANSMEMBRANE-CONDUCTANCE-REGULATOR
  • NUCLEOTIDE-BINDING DOMAIN
  • CYSTIC-FIBROSIS
  • CHLORIDE CHANNEL
  • R-DOMAIN
  • ATP HYDROLYSIS
  • MUTATION
  • RESCUE
  • DELTA-F508
  • REGION

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

Tools:

Journal Title:

Scientific Reports

Volume:

Volume 9, Number 1

Publisher:

, Pages 13460-13460

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2019, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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