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.

Data availability

All data are available within the Article, Supplementary Files and Appendices, or available from the corresponding authors on reasonable request. Source data for figures 2, 4d, 7b, Figure 3-Figure supplement 3, Figure 8a, Figure 8-Figure supplement 1b-c, Figure 8-Figure supplement 4b-c, Appendix 5 Table 1 and Appendix 5 Figure 1 are also provided with the paper.

Article and author information

Author details

  1. Krystel El Hage

    Department of Chemistry, Université Paris-Saclay, INSERM U1204, Evry, France
    For correspondence
    krystel.elhage@unibas.ch
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4837-3888
  2. Nicolas Babault

    SYNSIGHT, Evry, France
    Competing interests
    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.".
  3. Olek Maciejak

    Department of Chemistry, Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9594-9435
  4. Bénédicte Desforges

    Department of Chemistry, Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
  5. Pierrick Craveur

    SYNSIGHT, Evry, France
    Competing interests
    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.".
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9274-4944
  6. Emilie Steiner

    laboratoire structure activité des biomolécules normales et pathologiques, Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
  7. Juan Carlos Rengifo-Gonzalez

    SABNP, Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
  8. Hélène Henrie

    SYNSIGHT, Evry, France
    Competing interests
    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.".
  9. Marie-Jeanne Clement

    SABNP, Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
  10. Vandana Joshi

    laboratoire structure activité des biomolécules normales et pathologiques, Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
  11. Ahmed Bouhss

    Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6492-1429
  12. Liya Wang

    Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Université Paris-Saclay, INSERM U1204, Evry, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7119-8665
  13. Cyril Bauvais

    SYNSIGHT, Evry, France
    Competing interests
    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.".
  14. David Pastré

    SABNP, Université Paris-Saclay, INSERM U1204, Evry, France
    For correspondence
    david.pastre@univ-evry.fr
    Competing interests
    No competing interests declared.

Funding

HORIZON EUROPE Marie Sklodowska-Curie Actions (895024)

  • Krystel El Hage

Genopole (SATURNE 2020)

  • David Pastré

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. José D Faraldo-Gómez, National Institutes of Health, United States

Publication history

  1. Received: May 18, 2022
  2. Accepted: January 17, 2023
  3. Accepted Manuscript published: January 18, 2023 (version 1)

Copyright

© 2023, El Hage et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Krystel El Hage
  2. Nicolas Babault
  3. Olek Maciejak
  4. Bénédicte Desforges
  5. Pierrick Craveur
  6. Emilie Steiner
  7. Juan Carlos Rengifo-Gonzalez
  8. Hélène Henrie
  9. Marie-Jeanne Clement
  10. Vandana Joshi
  11. Ahmed Bouhss
  12. Liya Wang
  13. Cyril Bauvais
  14. David Pastré
(2023)
Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors
eLife 12:e80387.
https://doi.org/10.7554/eLife.80387

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