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Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors
RNA-protein interactions (RPIs) are promising targets for developing new molecules of therapeutic interest. Nevertheless, challenges arise from the lack of methods and feedback between computational and experimental techniques during the drug discovery process. Here, we tackle these challenges by de...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928419/ https://www.ncbi.nlm.nih.gov/pubmed/36651723 http://dx.doi.org/10.7554/eLife.80387 |
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author | El Hage, Krystel Babault, Nicolas Maciejak, Olek Desforges, Bénédicte Craveur, Pierrick Steiner, Emilie Rengifo-Gonzalez, Juan Carlos Henrie, Hélène Clement, Marie-Jeanne Joshi, Vandana Bouhss, Ahmed Wang, Liya Bauvais, Cyril Pastré, David |
author_facet | El Hage, Krystel Babault, Nicolas Maciejak, Olek Desforges, Bénédicte Craveur, Pierrick Steiner, Emilie Rengifo-Gonzalez, Juan Carlos Henrie, Hélène Clement, Marie-Jeanne Joshi, Vandana Bouhss, Ahmed Wang, Liya Bauvais, Cyril Pastré, David |
author_sort | El Hage, Krystel |
collection | PubMed |
description | RNA-protein interactions (RPIs) are promising targets for developing new molecules of therapeutic interest. Nevertheless, challenges arise from the lack of methods and feedback between computational and experimental techniques during the drug discovery process. Here, we tackle these challenges by developing a drug screening approach that integrates chemical, structural and cellular data from both advanced computational techniques and a method to score RPIs in cells for the development of small RPI inhibitors; and we demonstrate its robustness by targeting Y-box binding protein 1 (YB-1), a messenger RNA-binding protein involved in cancer progression and resistance to chemotherapy. This approach led to the identification of 22 hits validated by molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy of which 11 were found to significantly interfere with the binding of messenger RNA (mRNA) to YB-1 in cells. One of our leads is an FDA-approved poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor. This work shows the potential of our integrative approach and paves the way for the rational development of RPI inhibitors. |
format | Online Article Text |
id | pubmed-9928419 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-99284192023-02-15 Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors El Hage, Krystel Babault, Nicolas Maciejak, Olek Desforges, Bénédicte Craveur, Pierrick Steiner, Emilie Rengifo-Gonzalez, Juan Carlos Henrie, Hélène Clement, Marie-Jeanne Joshi, Vandana Bouhss, Ahmed Wang, Liya Bauvais, Cyril Pastré, David eLife Biochemistry and Chemical Biology RNA-protein interactions (RPIs) are promising targets for developing new molecules of therapeutic interest. Nevertheless, challenges arise from the lack of methods and feedback between computational and experimental techniques during the drug discovery process. Here, we tackle these challenges by developing a drug screening approach that integrates chemical, structural and cellular data from both advanced computational techniques and a method to score RPIs in cells for the development of small RPI inhibitors; and we demonstrate its robustness by targeting Y-box binding protein 1 (YB-1), a messenger RNA-binding protein involved in cancer progression and resistance to chemotherapy. This approach led to the identification of 22 hits validated by molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy of which 11 were found to significantly interfere with the binding of messenger RNA (mRNA) to YB-1 in cells. One of our leads is an FDA-approved poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor. This work shows the potential of our integrative approach and paves the way for the rational development of RPI inhibitors. eLife Sciences Publications, Ltd 2023-01-18 /pmc/articles/PMC9928419/ /pubmed/36651723 http://dx.doi.org/10.7554/eLife.80387 Text en © 2023, El Hage et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology El Hage, Krystel Babault, Nicolas Maciejak, Olek Desforges, Bénédicte Craveur, Pierrick Steiner, Emilie Rengifo-Gonzalez, Juan Carlos Henrie, Hélène Clement, Marie-Jeanne Joshi, Vandana Bouhss, Ahmed Wang, Liya Bauvais, Cyril Pastré, David Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors |
title | Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors |
title_full | Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors |
title_fullStr | Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors |
title_full_unstemmed | Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors |
title_short | Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors |
title_sort | targeting rna:protein interactions with an integrative approach leads to the identification of potent ybx1 inhibitors |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928419/ https://www.ncbi.nlm.nih.gov/pubmed/36651723 http://dx.doi.org/10.7554/eLife.80387 |
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