Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors
| Autor: | Krystel El Hage, Nicolas Babault, Olek Maciejak, Bénédicte Desforges, Pierrick Craveur, Emilie Steiner, Juan Carlos Rengifo-Gonzalez, Hélène Henrie, Marie-Jeanne Clement, Vandana Joshi, Ahmed Bouhss, Liya Wang, Cyril Bauvais, David Pastré |
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| Přispěvatelé: | Structure et activité des biomolécules normales et pathologiques (SABNP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Synsight |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | eLife eLife, 2023, 12, pp.e80387. ⟨10.7554/eLife.80387⟩ bioRxiv BioRxiv elife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.80387⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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