Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1784781333775515648 |
---|---|
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). |
format | Online Article Text |
id | pubmed-9436315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bidoulaure 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT bugaudolivier 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT merergoulven 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT coupetmatthieu 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT hatinisabelle 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT chirkinegor 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT karrisabrina 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT demaisstephane 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT francoispauline 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT cintratjeanchristophe 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases AT namyolivier 2guanidinoquinazolinepromotesthereadthroughofnonsensemutationsunderlyinghumangeneticdiseases |