Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 122, Issue -, Pages 429-435Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.06.048
Keywords
PTCs readthrough; CFIR gene; Nonsense mutation; Oxadiazoles; Cystic fibrosis
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Funding
- Italian Cystic Fibrosis Research Foundation, grant FFC [02/2011, 1/2014]
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Ataluren, also known as PTC124, is a 5-(fluorophenyI)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molecular dynamics simulations highlighting the importance of H-bonding and stacking pi-pi interactions. A series of non-acidic analogues of PTC124 were selected from a large database via a ligand-based virtual screening approach. Eight of them were synthesized and tested for their readthrough activity using the Fluc reporter harboring the UGA premature stop codon. The most active compound was further tested for suppression of the UGA nonsense mutation in the bronchial epithelial IB3.1 cell line carrying the W1282X mutation in the CFTR gene. (C) 2016 Elsevier Masson SAS. All rights reserved.
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