Uses
VX 809 is used in the stabilization of the CFTR protein used in the treatment of cystic fibrosis.
Definition
ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid with the aromatic amino group of 3-(6-amino-3-methylpyridin-2-yl)benzoic acid. Used for the treatment of cystic fi
rosis.
Biological Activity
vx-809 is a cftr corrector that partially restores the function of f508del-cftr. in fischer rat thyroid (frt) cells, it increases f508del-cftr maturation at ec50 of 0.1 μm, and elevates f508del-cftr–mediated chloride transport at ec50 of 0.5 μm [1]. it has no effect of other ion channels (herg), transporter (p-gp) and disease-causing mislocalized proteins (α1-antitrypsin z mutant) [1]. vx-809 stabilizes n-terminal fragment of cftr that contain msd1 by altering its protein conformation [2, 3].homozygous f508del-cftr is the most common mutation in cystic fibrosis (cf) patients, accounting for 66–70% of cf cases worldwide. in cultured human bronchial epithelial cells that are homozygous for f508del, vx-809 restored the cftr function and improved chloride and fluid transport [1]. the combination of cftr potentiators and vx-809 further improved the function of f508del-cftr [4].vx-809 has been tested in several
Mode of action
CF is a hereditary condition caused by mutations in the CFTR gene, which provides instructions for producing an ion channel protein called CF transmembrane conductance regulator (CFTR). These mutations cause defects in the CFTR protein, which disrupts the normal salt-water transport across the cell membrane and produces thick, sticky mucus that may accumulate in different organs, including the lungs. One of the common mutations in the CFTR gene is the so-called F508del mutation, which results in a defective misfolded CFTR protein. The misfolded protein is degraded by the cell before it can reach the cell membrane. Even if some of the defective proteins reach the cell membrane, they are unable to open correctly and allow the passage of chloride ions. Lumacaftor and ivacaftor work together to restore the function of the CFTR protein at the cell membrane. Lumacaftor increases the stability of defective CFTR proteins, helping them reach the cell membrane and stay there longer. But because it does not address the problem with the opening of the channel, lumacaftor is generally used in combination with ivacaftor, which acts on the defective proteins, helping them to open more often so that the salt-water balance across the cell surface is restored.
