A coronavirus assembly inhibitor that targets the viral membrane protein

• 成果类型: Article
• 署名作者: Laporte, Manon; Jochmans, Dirk; Bardiot, Dorothee; Desmarets, Lowiese; Debski-Antoniak, Oliver J.; Mizzon, Giulia; Abdelnabi, Rana; Leyssen, Pieter; Chiu, Winston; Zhang, Zhikuan; Nomura, Norimichi; Boland, Sandro; Ohto, Umeharu; Stahl, Yannick; Wuyts, Jurgen; De Jonghe, Steven; Stevaert, Annelies; van Hemert, Martijn J.; Bontes, Brenda W.; Wanningen, Patrick; Groenewold, G. J. Mirjam; Zegar, Aneta; Owczarek, Katarzyna; Joshi, Sanjata; Koukni, Mohamed; Arzel, Philippe; Klaassen, Hugo; Vanherck, Jean-Christophe; Vandecaetsbeek, Ilse; Cremers, Niels; Donckers, Kim; Francken, Thibault; Van Buyten, Tina; Rymenants, Jasper; Schepers, Joost; Pyrc, Krzysztof; Hilgenfeld, Rolf; Dubuisson, Jean; Bosch, Berend-Jan; Van Kuppeveld, Frank; Eydoux, Cecilia; Decroly, Etienne; Canard, Bruno; Naesens, Lieve; Weynand, Birgit; Snijder, Eric J.; Belouzard, Sandrine; Shimizu, Toshiyuki; Bartenschlager, Ralf; Hurdiss, Daniel L.; Marchand, Arnaud; Chaltin, Patrick; Neyts, Johan
• 署名单位: KU Leuven; Universite de Lille; Pasteur Network; Institut Pasteur Lille; CHU Lille; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Utrecht University; Ruprecht Karls University Heidelberg; German Center for Infection Research; KU Leuven; University of Tokyo; Kyoto University; KU Leuven; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Jagiellonian University; University of Lubeck; German Center for Infection Research; University of Lubeck; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; KU Leuven; Helmholtz Association; German Cancer Research Center (DKFZ); KU Leuven
• 刊物名称: Nature
• ISSN/ISSBN: 0028-0988
• DOI: 10.1038/s41586-025-08773-x
• 发表日期: 2025-04-10
• 关键词: particle cryo-em; Visualization; virus; SARS; replication; refinement

摘要

The coronavirus membrane protein (M) is the main organizer of coronavirus assembly1, 2-3. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.