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A condensate-hardening drug blocks RSV replication in vivo

Author

Listed:
  • Jennifer Risso-Ballester

    (Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I))

  • Marie Galloux

    (Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay)

  • Jingjing Cao

    (Shandong University)

  • Ronan Goffic

    (Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay)

  • Fortune Hontonnou

    (Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay)

  • Aude Jobart-Malfait

    (Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I))

  • Aurore Desquesnes

    (Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I))

  • Svenja M. Sake

    (Helmholtz International Lab for Anti-Infectives, Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research)

  • Sibylle Haid

    (Helmholtz International Lab for Anti-Infectives, Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research)

  • Miaomiao Du

    (Shandong University)

  • Xiumei Zhang

    (Shandong University)

  • Huanyun Zhang

    (Shandong University)

  • Zhaoguo Wang

    (Qingdao Municipal Center for Disease Control and Prevention)

  • Vincent Rincheval

    (Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I))

  • Youming Zhang

    (Shandong University)

  • Thomas Pietschmann

    (Helmholtz International Lab for Anti-Infectives, Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research)

  • Jean-François Eléouët

    (Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay)

  • Marie-Anne Rameix-Welti

    (Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I)
    Université Paris Saclay, Hôpital Ambroise Paré, Laboratoire de Microbiologie)

  • Ralf Altmeyer

    (Shandong University
    University of Hong Kong)

Abstract

Biomolecular condensates have emerged as an important subcellular organizing principle1. Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm2,3. IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation4,5. Here we report that the steroidal alkaloid cyclopamine and its chemical analogue A3E inhibit RSV replication by disorganizing and hardening IB condensates. The actions of cyclopamine and A3E were blocked by a point mutation in the RSV transcription factor M2-1. IB disorganization occurred within minutes, which suggests that these molecules directly act on the liquid properties of the IBs. A3E and cyclopamine inhibit RSV in the lungs of infected mice and are condensate-targeting drug-like small molecules that have in vivo activity. Our data show that condensate-hardening drugs may enable the pharmacological modulation of not only many previously undruggable targets in viral replication but also transcription factors at cancer-driving super-enhancers6.

Suggested Citation

  • Jennifer Risso-Ballester & Marie Galloux & Jingjing Cao & Ronan Goffic & Fortune Hontonnou & Aude Jobart-Malfait & Aurore Desquesnes & Svenja M. Sake & Sibylle Haid & Miaomiao Du & Xiumei Zhang & Huan, 2021. "A condensate-hardening drug blocks RSV replication in vivo," Nature, Nature, vol. 595(7868), pages 596-599, July.
    • Handle: RePEc:nat:nature:v:595:y:2021:i:7868:d:10.1038_s41586-021-03703-z
    DOI: 10.1038/s41586-021-03703-z
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    Cited by:

    1. Lorène Gonnin & Ambroise Desfosses & Maria Bacia-Verloop & Didier Chevret & Marie Galloux & Jean-François Éléouët & Irina Gutsche, 2023. "Structural landscape of the respiratory syncytial virus nucleocapsids," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Jingru Fang & Guillaume Castillon & Sebastien Phan & Sara McArdle & Chitra Hariharan & Aiyana Adams & Mark H. Ellisman & Ashok A. Deniz & Erica Ollmann Saphire, 2023. "Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Svenja M. Sake & Xiaoyu Zhang & Manoj Kumar Rajak & Melanie Urbanek-Quaing & Arnaud Carpentier & Antonia P. Gunesch & Christina Grethe & Alina Matthaei & Jessica Rückert & Marie Galloux & Thibaut Larc, 2024. "Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Ibraheem Alshareedah & Mahdi Muhammad Moosa & Matthew Pham & Davit A. Potoyan & Priya R. Banerjee, 2021. "Programmable viscoelasticity in protein-RNA condensates with disordered sticker-spacer polypeptides," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Jack D. Whitehead & Hortense Decool & Cédric Leyrat & Loic Carrique & Jenna Fix & Jean-François Eléouët & Marie Galloux & Max Renner, 2023. "Structure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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