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High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
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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
Summary
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.
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