Chemistry & Biology
Volume 20, Issue 7, 25 July 2013, Pages 943-955
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Article
Revertants, Low Temperature, and Correctors Reveal the Mechanism of F508del-CFTR Rescue by VX-809 and Suggest Multiple Agents for Full Correction

https://doi.org/10.1016/j.chembiol.2013.06.004Get rights and content
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Highlights

  • VX-809 is additive to 4RK and G550E revertants but to a lesser extent with R1070W

  • Rescue of F508del-CFTR by all three correctors is additive to low temperature

  • VX-809 is additive to VRT-325 and Corr-4a correctors to rescue F508del-CFTR

  • Experimental data fit to a model in which VX-809 binds at the NBD1:ICL4 interface

Summary

Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA). Herein, we assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its MoA. We explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR. Our experimental and modeling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR.

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Present address: Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA