A condensate-hardening drug blocks RSV replication in vivo

Autor: Zhaoguo Wang, Ronan Le Goffic, Jean-François Eléouët, Ralf Altmeyer, Jennifer Risso-Ballester, Cao Jingjing, Miaomiao Du, Sibylle Haid, Marie Galloux, Huanyun Zhang, Aurore Desquesnes, Youming Zhang, Thomas Pietschmann, Fortune Hontonnou, Vincent Rincheval, Aude Jobart-Malfait, Svenja M. Sake, Marie-Anne Rameix-Welti, Xiumei Zhang
Přispěvatelé: Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Shandong University, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), Qingdao Municipal Center for Disease Control and Prevention, Partenaires INRAE, Hôpital Ambroise Paré [AP-HP], The University of Hong Kong (HKU), Fondation Air Liquide, China - 111 Project B16030, ATIP-AVENIR INSERM and Fondation Del Duca-Institut de France, People’s Livelihood Technology Project of Qingdao City (17-3-3-2-nsh), Ile de France region (SESAME), Natural Science Foundation of China Youth Project (31900147), Sino-German Helmholtz International Lab grant (10000089395401), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Région Île-de-France, Natural Science Foundation of China Youth Project: 31900147, Fondation Air Liquide, Ministry of Education, China - 111 Project: B16030, ATIP-AVENIR INSERM program, Fondation Del Duca-Institut de France grant, Sino-German Helmholtz International Lab grant: 10000089395401, People's Livelihood Technology Project of Qingdao City: 17-3-3-2-nsh, Le Goffic, Ronan
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Nature
Nature, Nature Publishing Group, 2021, 595 (7868), pp.596-599. ⟨10.1038/s41586-021-03703-z⟩
ISSN: 0028-0836
1476-4679
1476-4687
DOI: 10.1038/s41586-021-03703-z⟩
Popis: 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. Cyclopamine and its chemical analogue A3E inhibit replication of human respiratory syncytial virus (RSV) by hardening the liquid–liquid phase-separated inclusion bodies, resulting in the inhibition of virus replication in the lungs of RSV-infected mice.
Databáze: OpenAIRE
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