title: Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction.
abstract: 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.
authors.affiliation: Faculty of Sciences, Center for Biodiversity, Functional, and Integrative Genomics, University of Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Farinha
authors.forename: John
authors.initials: J
authors.lastname: King-Underwood
authors.forename: Marisa
authors.initials: M
authors.lastname: Sousa
authors.forename: Ana Raquel
authors.initials: AR
authors.lastname: Correia
authors.forename: Bárbara J
authors.initials: BJ
authors.lastname: Henriques
authors.forename: Mónica
authors.initials: M
authors.lastname: Roxo-Rosa
authors.forename: Ana Carina
authors.initials: AC
authors.lastname: Da Paula
authors.forename: Jonathan
authors.initials: J
authors.lastname: Williams
authors.forename: Simon
authors.initials: S
authors.lastname: Hirst
authors.forename: Cláudio M
authors.initials: CM
authors.lastname: Gomes
authors.forename: Margarida D
authors.initials: MD
authors.lastname: Amaral
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009711:Nucleotides / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion / Q000187:drug effects*; D013696:Temperature
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; D009711:Nucleotides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor