title: Exploring the readthrough of nonsense mutations by non-acidic Ataluren analogues selected by ligand-based virtual screening.
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.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Pibiri
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. Electronic address: laura.lentini@unipa.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Lentini
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tutone
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Melfi
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy; Istituto EuroMediterraneo di Scienza e Tecnologia (IEMEST), Via Emerico Amari 123, 90139 Palermo, Italy. Electronic address: andrea.pace@unipa.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pace
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy; Centro di OncoBiologia Sperimentale (COBS), via San Lorenzo Colli, 90145 Palermo, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Di Leonardo
mesh_terms: D018389:Codon, Nonsense / Q000187:drug effects*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D010069:Oxadiazoles; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C515878:ataluren
keywords: CFTR gene; Cystic fibrosis; Nonsense mutation; Oxadiazoles; PTCs readthrough