VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.
Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.
Department of Cell Biology and University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 Vertex Pharmaceuticals, San Diego, CA 92121.
Hong Yu
HY
Ren
Diane E
DE
Grove
Oxana
O
De La Rosa
Scott A
SA
Houck
Pattarawut
P
Sopha
Fredrick
F
Van Goor
Beth J
BJ
Hoffman
Douglas M
DM
Cyr
D000631:Aminopyridines / Q000008:administration & dosage*; D052117:Benzodioxoles / Q000008:administration & dosage*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D000631:Aminopyridines; D052117:Benzodioxoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor