生物活性

• 描述Nonsense mutations have been implicated in numerous inherited diseases and several cancers. For example, cystic fibrosis (CF) is a common autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. PTC-124 is an orally bioavailable compound that promotes readthrough of premature translation termination codons, suggesting its potential to treat genetic diseases caused by nonsense mutations like mutations in CFTR^[3]. The minimal concentration of PTC-124 showing discernable readthrough was 0.01–0.1 μM (2.8-28 ng/ml). And it promoted dose-dependent readthrough of all three nonsense codons in stable cell lines harbouring LUC-190 nonsense alleles^[4]. In a mouse model with CF, s.c. injection or oral administration of PTC-124 (60 mg/kg) to Cftr-/- mice expressing a human CFTR-G542X transgene suppressed the G542X nonsense mutation and restored a significant amount of human (h)CFTR protein and function. In addition, PTC-124 (60 mg/kg by s.c. injection or a liquid diet containing 0.9 mg/ml PTC-124) treatment restored 24-29% of the average cAMP-stimulated transepithelial chloride currents observed in wild-type mice. These results indicate that PTC-124 can effectively suppress the hCFTR-G542X nonsense mutation in vivo^[3].