MilliporeSigma
  • Home
  • Search Results
  • Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives.

Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives.

European journal of medicinal chemistry (2015-07-06)
Ivana Pibiri, Laura Lentini, Raffaella Melfi, Giulia Gallucci, Andrea Pace, Angelo Spinello, Giampaolo Barone, Aldo Di Leonardo
ABSTRACT

Premature stop codons are the result of nonsense mutations occurring within the coding sequence of a gene. These mutations lead to the synthesis of a truncated protein and are responsible for several genetic diseases. A potential pharmacological approach to treat these diseases is to promote the translational readthrough of premature stop codons by small molecules aiming to restore the full-length protein. The compound PTC124 (Ataluren) was reported to promote the readthrough of the premature UGA stop codon, although its activity was questioned. The potential interaction of PTC124 with mutated mRNA was recently suggested by molecular dynamics (MD) studies highlighting the importance of H-bonding and stacking π-π interactions. To improve the readthrough activity we changed the fluorine number and position in the PTC124 fluoroaryl moiety. The readthrough ability of these PTC124 derivatives was tested in human cells harboring reporter plasmids with premature stop codons in H2BGFP and FLuc genes as well as in cystic fibrosis (CF) IB3.1 cells with a nonsense mutation. Maintaining low toxicity, three of these molecules showed higher efficacy than PTC124 in the readthrough of the UGA premature stop codon and in recovering the expression of the CFTR protein in IB3.1 cells from cystic fibrosis patient. Molecular dynamics simulations performed with mutated CFTR mRNA fragments and active or inactive derivatives are in agreement with the suggested interaction of PTC124 with mRNA.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium dodecyl sulfate solution, BioUltra, for molecular biology, 10% in H2O
Sigma-Aldrich
Sodium dodecyl sulfate solution, BioUltra, for molecular biology, 20% in H2O
Sigma-Aldrich
Sodium dodecyl sulfate, BioReagent, suitable for electrophoresis, for molecular biology, ≥98.5% (GC)
Sigma-Aldrich
Sodium dodecyl sulfate, 92.5-100.5% based on total alkyl sulfate content basis
Sigma-Aldrich
Sodium dodecyl sulfate, ReagentPlus®, ≥98.5% (GC)
Sigma-Aldrich
Sodium dodecyl sulfate, ≥99.0% (GC), dust-free pellets
Sigma-Aldrich
Sodium dodecyl sulfate, ≥90%
Sigma-Aldrich
Sodium dodecyl sulfate, BioUltra, for molecular biology, ≥99.0% (GC)
Sigma-Aldrich
Sodium dodecyl sulfate, ≥98.0% (GC)
Sigma-Aldrich
Sodium dodecyl sulfate, tested according to NF, mixture of sodium alkyl sulfates consisting mainly of sodium dodecyl sulfate
Sigma-Aldrich
Sodium dodecyl sulfate, ACS reagent, ≥99.0%
Sigma-Aldrich
Sodium dodecyl sulfate, BioXtra, ≥99.0% (GC)
Supelco
Sodium dodecyl sulfate, dust-free pellets, suitable for electrophoresis, for molecular biology, ≥99.0% (GC)
Sigma-Aldrich
Sodium dodecyl sulfate, BioReagent, suitable for electrophoresis, for molecular biology, ≥98.5% (GC), free-flowing, Redi-Dri