CFTR translational fidelity (class I
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 , .
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