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Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target

Riccardo Perriera1, Emanuele Vitale1, Ivana Pibiri1

  • 1Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy.

International Journal of Molecular Sciences
|October 28, 2023
PubMed

Insights

New drugs targeting genetic diseases show promise. These translational readthrough-inducing drugs (TRIDs) specifically correct premature termination codons (PTCs) without affecting natural termination codons (NTCs).

Area of Science:

  • Molecular Biology
  • Genetics
  • Pharmacology

Background:

  • Nonsense mutations lead to genetic disorders like cystic fibrosis and Duchenne muscular dystrophy by creating premature termination codons (PTCs) in mRNA.
  • Nonsense suppression therapy using translational readthrough-inducing drugs (TRIDs) offers a potential treatment by enabling the synthesis of full-length proteins.

Purpose of the Study:

  • To investigate the potential off-target effects of novel oxadiazole-core TRIDs (NV848, NV914, NV930) on natural termination codons (NTCs).
  • To assess the specificity of these TRIDs for PTCs versus NTCs.

Main Methods:

  • In vitro assessment of NV molecule treatment on p53 protein molecular weight and functionality.
  • In vitro evaluation of the impact of NV molecules on the molecular weights of housekeeping proteins Cys-C and β2M.

Main Results:

  • NV848, NV914, and NV930 did not induce any translational alterations in the tested in vitro systems.
  • No significant readthrough was observed at natural termination codons (NTCs) upon treatment with the NV molecules.

Conclusions:

  • The novel oxadiazole-core TRIDs (NV848, NV914, NV930) demonstrate specific activity at premature termination codons (PTCs).
  • These TRIDs exhibit an undetectable effect on natural termination codons (NTCs), suggesting a favorable safety profile for nonsense suppression therapy.
Keywords:
genetic diseasesnonsenseprecision medicinepremature termination codons oxadiazoletranslational readthrough

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