A condensate-hardening drug blocks RSV replication in vivo

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, Huanyun Zhang, Zhaoguo Wang, Vincent Rincheval, Youming Zhang, Thomas Pietschmann, Jean-François Eléouët (), Marie-Anne Rameix-Welti () and Ralf Altmeyer ()
Additional contact information
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)
Ralf Altmeyer: Shandong University

Nature, 2021, vol. 595, issue 7868, 596-599

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03703-z

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