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

Ivana Pibiri1, Laura Lentini2, Raffaella Melfi2

  • 1Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 17, 90128 Palermo, Italy; Istituto EuroMediterraneo di Scienza e Tecnologia (IEMEST), Via Emerico Amari 123, 90139 Palermo, Italy.

European Journal of Medicinal Chemistry
|July 6, 2015
PubMed

Insights

Researchers developed novel compounds that effectively promote the readthrough of premature stop codons, a key factor in genetic diseases. These molecules restore full-length protein synthesis, offering a promising therapeutic strategy for conditions like cystic fibrosis.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Genetics

Background:

  • Nonsense mutations create premature stop codons, leading to truncated proteins and genetic diseases.
  • Translational readthrough by small molecules is a potential therapeutic strategy to restore protein function.
  • The efficacy of PTC124 (Ataluren) in readthrough has been debated, with recent studies suggesting mRNA interactions.

Purpose of the Study:

  • To design and synthesize novel PTC124 derivatives with improved premature stop codon readthrough activity.
  • To evaluate the efficacy of these derivatives in cellular models of genetic diseases.
  • To investigate the molecular interactions between PTC124 derivatives and mRNA.

Main Methods:

  • Synthesis of PTC124 derivatives with modified fluoroaryl moieties.
  • Assay of readthrough activity in human cells using reporter gene plasmids (H2BGFP, FLuc).
  • Assessment of compound efficacy in cystic fibrosis (CF) IB3.1 cells with a nonsense mutation.
  • Molecular dynamics (MD) simulations of drug-mRNA interactions.

Main Results:

  • Three novel PTC124 derivatives demonstrated higher efficacy than PTC124 in UGA premature stop codon readthrough.
  • These derivatives showed increased recovery of CFTR protein expression in cystic fibrosis patient-derived IB3.1 cells.
  • The developed compounds exhibited low toxicity.
  • MD simulations supported the proposed interaction mechanism between PTC124 derivatives and mutated mRNA.

Conclusions:

  • Modified PTC124 derivatives show enhanced therapeutic potential for genetic diseases caused by nonsense mutations.
  • These compounds effectively promote translational readthrough and restore protein expression with low toxicity.
  • The findings support the development of small molecules targeting mRNA for treating genetic disorders.
Keywords:
CFTR geneCystic fibrosisFluorinated oxadiazoleGreen fluorescent proteinNonsense mutationPTCs readthrough

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