期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：35
DOI：10.1073/pnas.2122004119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Nonsense mutations account for approximately 11% of all described gene lesions causing human inherited diseases. This premature termination codon (PTC) leads to the premature arrest of translation that generates a truncated peptide and the degradation of the corresponding mRNA through the nonsense-mediated mRNA decay (NMD) pathway. The possibility of restoring the protein expression by promoting PTC readthrough using drugs appears to be an important therapeutic strategy. Unfortunately, this strategy is limited by the small number of molecules known to promote PTC readthrough without affecting normal translation termination. In this work, we identify a new molecule, TLN468, that promotes a high level of PTC readthrough without a detectable effect on normal stop codons.
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-guanidino-quinazoline (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).
