2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases - CEA - Commissariat à l’énergie atomique et aux énergies alternatives Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2022

2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases

Résumé

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).

Domaines

Chimie

Dates et versions

cea-04352610 , version 1 (19-12-2023)

Identifiants

Citer

Laure Bidou, Olivier Bugaud, Goulven Merer, Matthieu Coupet, Isabelle Hatin, et al.. 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119 (35), ⟨10.1073/pnas.2122004119⟩. ⟨cea-04352610⟩
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