Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System
Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requ...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2801 |
| _version_ | 1797574555043102720 |
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| author | Julie Carrard Fiona Ratajczak Joséphine Elsens Catherine Leroy Rebekah Kong Lucie Geoffroy Arnaud Comte Guy Fournet Benoît Joseph Xiubin Li Sylvie Moebs-Sanchez Fabrice Lejeune |
| author_facet | Julie Carrard Fiona Ratajczak Joséphine Elsens Catherine Leroy Rebekah Kong Lucie Geoffroy Arnaud Comte Guy Fournet Benoît Joseph Xiubin Li Sylvie Moebs-Sanchez Fabrice Lejeune |
| author_sort | Julie Carrard |
| collection | DOAJ |
| description | Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires molecules capable of inhibiting NMD effectively without inducing toxicity. We have built a new screening system and used it to identify and validate two new molecules that can inhibit NMD at least as effectively as cycloheximide, a reference NMD inhibitor molecule. These new NMD inhibitors show no cellular toxicity at tested concentrations and have a working concentration between 6.2 and 12.5 µM. We have further validated this NMD-inhibiting property in a physiopathological model of lung cancer in which the <i>TP53</i> gene carries a nonsense mutation. These new molecules may potentially be of interest in the development of therapies for genetic diseases caused by a nonsense mutation. |
| first_indexed | 2024-03-10T21:24:08Z |
| format | Article |
| id | doaj.art-05e2ba02ef9c46fb8388786117f2811b |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:24:08Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-05e2ba02ef9c46fb8388786117f2811b2023-11-19T15:47:19ZengMDPI AGBiomedicines2227-90592023-10-011110280110.3390/biomedicines11102801Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening SystemJulie Carrard0Fiona Ratajczak1Joséphine Elsens2Catherine Leroy3Rebekah Kong4Lucie Geoffroy5Arnaud Comte6Guy Fournet7Benoît Joseph8Xiubin Li9Sylvie Moebs-Sanchez10Fabrice Lejeune11Univ. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, ICBMS, UMR 5246, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, ICBMS, UMR 5246, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, ICBMS, UMR 5246, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, ICBMS, UMR 5246, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, ICBMS, UMR 5246, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, FranceUniv. Lille, CNRS, Inserm, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceNonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires molecules capable of inhibiting NMD effectively without inducing toxicity. We have built a new screening system and used it to identify and validate two new molecules that can inhibit NMD at least as effectively as cycloheximide, a reference NMD inhibitor molecule. These new NMD inhibitors show no cellular toxicity at tested concentrations and have a working concentration between 6.2 and 12.5 µM. We have further validated this NMD-inhibiting property in a physiopathological model of lung cancer in which the <i>TP53</i> gene carries a nonsense mutation. These new molecules may potentially be of interest in the development of therapies for genetic diseases caused by a nonsense mutation.https://www.mdpi.com/2227-9059/11/10/2801nonsense mutationsmall moleculestherapynonsense-mediated mRNA decaygenetic disease |
| spellingShingle | Julie Carrard Fiona Ratajczak Joséphine Elsens Catherine Leroy Rebekah Kong Lucie Geoffroy Arnaud Comte Guy Fournet Benoît Joseph Xiubin Li Sylvie Moebs-Sanchez Fabrice Lejeune Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System Biomedicines nonsense mutation small molecules therapy nonsense-mediated mRNA decay genetic disease |
| title | Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System |
| title_full | Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System |
| title_fullStr | Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System |
| title_full_unstemmed | Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System |
| title_short | Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System |
| title_sort | identifying potent nonsense mediated mrna decay inhibitors with a novel screening system |
| topic | nonsense mutation small molecules therapy nonsense-mediated mRNA decay genetic disease |
| url | https://www.mdpi.com/2227-9059/11/10/2801 |
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