Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors
- PMID: 36651723
- DOI: 10.7554/eLife.80387
Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors
Abstract
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.
Keywords: biochemistry; chemical biology; molecular biophysics; structural biology.
© 2023, El Hage et al.
Conflict of interest statement
KE, OM, BD, ES, JR, MC, VJ, AB, LW, DP The other authors declare that no competing interests exist. NB Nicolas Babault, Synsight has acquired a license for the MT bench" patent (WO2016012451A1) concerning the industrial applications. Nicolas Babault is affiliated with SYNSIGHT. The author has no financial interests to declare.". PC Pierrick Craveur, Synsight has acquired a license for the MT bench" patent (WO2016012451A1) concerning the industrial applications. Pierrick Craveur is affiliated with SYNSIGHT. The author has no financial interests to declare.". HH Hélène Henrie, Synsight has acquired a license for the MT bench" patent (WO2016012451A1) concerning the industrial applications. Hélène Henrie is affiliated with SYNSIGHT. The author has no financial interests to declare.". CB Cyril Bauvais, Synsight has acquired a license for the MT bench" patent (WO2016012451A1) concerning the industrial applications. Cyril Bauvais is affiliated with SYNSIGHT. The author has no financial interests to declare.".
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