ArticleProceedings of the National Academy of Sciences of the United States of America2016
Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 135 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
135 citing papers in PubMed, 1 synthesis or guideline pooled it, 222 citations in OpenAlex.
- RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges.Pharmacological reviews · 2020Pooled it
- Confirmatory long-term efficacy and safety results of ataluren in patients with nmDMD from Study 041, an international, randomized, double-blind, placebo-controlled, Phase III trial.Journal of comparative effectiveness research · 2025Trial
- Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF).Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2020Trial
- Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity.Journal of immunology (Baltimore, Md. : 1950) · 2019Trial
- Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy.Science advances · 2026Article
- Pharmacological readthrough and base editing forMolecular therapy. Nucleic acids · 2026Article
- Programmed repair of disease-causing UGA premature termination codons in mammalian brain.Nucleic acids research · 2026Article
- Identification of small molecules that enhance aminoglycoside-mediated suppression ofMolecular therapy. Oncology · 2026Article
- RFFL-mediated protein quality control limits functional rescue of TRID-CFTR modulator combination therapy for cystic fibrosis nonsense mutations.Cellular and molecular life sciences : CMLS · 2026Article
- Current Trends in Duchenne Muscular Dystrophy Research and Therapy: 3D Cardiac Modelling.Journal of cachexia, sarcopenia and muscle · 2026Review
- Ribosomal read through as an alternative therapy for patients with hemophilia with nonsense mutations.Journal of thrombosis and haemostasis : JTH · 2026Article
- Identity, functional consequences, and context effects of amino acids inserted during suppression of CFTR nonsense mutations.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2026Article
- Precision therapeutic tRNA rescue of nonsense mutation R166X inJournal of precision medicine (Amsterdam, Netherlands) · 2025Article
- Molecular and genetic characteristics of patients from the National Registry of Duchenne/Becker Muscular Dystrophy in the Russian Federation: Pilot analysis.Journal of neuromuscular diseases · 2025Observational
- Review
- High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.Nucleic acids research · 2025Article
- A precision medicine approach to primary immunodeficiency disease: Ataluren strikes nonsense mutations once again.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.Nucleic acids research · 2025Article
- Emerging concepts in the molecular cell biology and functions of mammalian erythrocytes.The Journal of biological chemistry · 2025Review
- Article
75 more citing papers are in PubMed but not listed here.
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16 authors at 3 institutions in 1 country.
Funding
Abstract
A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren's likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren's retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.