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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
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.
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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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