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

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 read...

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Autores principales: Bidou, Laure, Bugaud, Olivier, Merer, Goulven, Coupet, Matthieu, Hatin, Isabelle, Chirkin, Egor, Karri, Sabrina, Demais, Stéphane, François, Pauline, Cintrat, Jean-Christophe, Namy, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436315/
https://www.ncbi.nlm.nih.gov/pubmed/35994666
http://dx.doi.org/10.1073/pnas.2122004119
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author Bidou, Laure
Bugaud, Olivier
Merer, Goulven
Coupet, Matthieu
Hatin, Isabelle
Chirkin, Egor
Karri, Sabrina
Demais, Stéphane
François, Pauline
Cintrat, Jean-Christophe
Namy, Olivier
author_facet Bidou, Laure
Bugaud, Olivier
Merer, Goulven
Coupet, Matthieu
Hatin, Isabelle
Chirkin, Egor
Karri, Sabrina
Demais, Stéphane
François, Pauline
Cintrat, Jean-Christophe
Namy, Olivier
author_sort Bidou, Laure
collection PubMed
description 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).
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spelling pubmed-94363152022-09-02 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases Bidou, Laure Bugaud, Olivier Merer, Goulven Coupet, Matthieu Hatin, Isabelle Chirkin, Egor Karri, Sabrina Demais, Stéphane François, Pauline Cintrat, Jean-Christophe Namy, Olivier Proc Natl Acad Sci U S A Biological Sciences 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). National Academy of Sciences 2022-08-22 2022-08-30 /pmc/articles/PMC9436315/ /pubmed/35994666 http://dx.doi.org/10.1073/pnas.2122004119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Bidou, Laure
Bugaud, Olivier
Merer, Goulven
Coupet, Matthieu
Hatin, Isabelle
Chirkin, Egor
Karri, Sabrina
Demais, Stéphane
François, Pauline
Cintrat, Jean-Christophe
Namy, Olivier
2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
title 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
title_full 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
title_fullStr 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
title_full_unstemmed 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
title_short 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
title_sort 2-guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436315/
https://www.ncbi.nlm.nih.gov/pubmed/35994666
http://dx.doi.org/10.1073/pnas.2122004119
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