Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 35, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2122004119
Keywords
ribosome; premature termination codon; stop codon readthrough; genetic disease; dystrophin mutations
Categories
Funding
- French foundation ARC [PJA20131200234]
- Vaincre la Mucoviscidose [RF20180502275]
- ANR [17-CE12-0024, 19-CE12-0004-02]
- AFM-Telethon [19660, 20531]
- French foundation FRM [FDT20150532470]
- AFM-Telethon
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In this study, a new drug was developed and evaluated for its clinical potential in treating genetic diseases caused by premature termination codons (PTCs). The drug, TLN468, was found to be more effective than the currently used gentamicin and acted on a broader range of sequences without affecting normal stop codon readthrough.
Premature termination codons (PTCs) account for 10 to 20% of genetic diseases in humans. The gene inactivation resulting from PTCs can be counteracted by the use of drugs stimulating PTC readthrough, thereby restoring production of the full-length protein. However, a greater chemical variety of readthrough inducers is required to broaden the medical applications of this therapeutic strategy. In this study, we developed a reporter cell line and performed high-throughput screening (HTS) to identify potential readthrough inducers. After three successive assays, we isolated 2-guanidinoquinazoline (TLN468). We assessed the clinical potential of this drug as a potent readthrough inducer on the 40 PTCs most frequently responsible for Duchenne muscular dystrophy (DMD). We found that TLN468 was more efficient than gentamicin, and acted on a broader range of sequences, without inducing the readthrough of normal stop codons (TC).
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