CFTR, PTC124, Small 40S subunit, mRNA, Large 60S subunit, DNA, <cytosol> Cl('-) = <extracellular region> Cl('-), 6.1.1.-, Gentamicin cytosol, AMP-aminoacid, tRNA, Cl('-) cytosol, aminoacid*(tRNA), Tobramycin cytosol, mRNA, mRNA, Cl('-) extracellular region, Amikacin cytosol
CFTR translational fidelity (class I mutations)
Cystic Fibrosis (CF) is a potentially lethal genetic disease that typically results in the development of bronchial inflammation, bronchiectasis, progressive loss of lung function and, ultimately, death. CF is caused by genetic defects in Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene which encodes a chloride channel regulating chloride transport in the lung .
More than 1000 mutations of the CFTR gene have been identified so far. Studies suggested that different mutations cause defects in production and function of the CFTR protein that involve different molecular mechanisms. The mutations are classified according to their molecular pathology. Class I mutations impair protein synthesis (e.g., premature termination signals, and truncated or unstable protein) and lead to lack of CFTR chloride channels. G542X, R553X, W1282X are the examples of class I mutations , .
Aminoglycoside antibiotics (e.g., Gentamicin , , Tobramycin , Amikacin  ) reduce fidelity of translation by inhibition of the ribosomal 'proofreading'. These antibiotics bind to the specific site on the ribosomal RNA and disrupt codon-anticodon recognition at the aminoacid*(tRNA) acceptor site. This causes extensive misreading of the mRNA code, enabling insertion of alternative amino acids at the site of the mutated codon. This substitution is not fully efficient; a fraction of normal full-length transcript is produced .
Another drug impairing translational fidelity is the PTC124, a 284.24Da achiral, 1,2,4-oxadiazole linked to fluorobenzene and benzoic acid rings. This compound has no structural similarity to aminoglycosides or other clinically developed drugs, and its anhydrous free carboxylic acid form, despite having low aqueous solubility, is orally bioavailable when prepared in aqueous suspension. PTC124 promotes read-through of premature termination CFTR without affecting normal termination .