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MARCO TUTONE

Exploring the readthrough of nonsense mutations by non-acidic Ataluren analogues selected by ligand-based virtual screening

  • Authors: Pibiri, I.; Lentini, L.; Tutone, M.; Melfi, R.; Pace, A.; Di Leonardo, A.
  • Publication year: 2016
  • Type: Articolo in rivista (Articolo in rivista)
  • Key words: CFTR gene; Cystic fibrosis; Nonsense mutation; Oxadiazoles; PTCs readthrough; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology
  • OA Link: http://hdl.handle.net/10447/193210

Abstract

Ataluren, also known as PTC124, is a 5-(fluorophenyl)-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 π−π 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.