A coronavirus assembly inhibitor that targets the viral membrane protein
The coronavirus membrane protein (M) is the main organizer of coronavirus assembly1-3. 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...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2025
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| In: |
Nature
Year: 2025, Jahrgang: 640, Heft: 8058, Pages: 514-523 |
| ISSN: | 1476-4687 |
| DOI: | 10.1038/s41586-025-08773-x |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41586-025-08773-x Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41586-025-08773-x 
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| Verfasserangaben: | Manon Laporte, Dirk Jochmans, Dorothée Bardiot, Lowiese Desmarets, Oliver J. Debski-Antoniak, Giulia Mizzon, Rana Abdelnabi, Pieter Leyssen, Winston Chiu, Zhikuan Zhang, Norimichi Nomura, Sandro Boland, Umeharu Ohto, Yannick Stahl, Jurgen Wuyts, Steven De Jonghe, Annelies Stevaert, Martijn J. van Hemert, Brenda W. Bontes, Patrick Wanningen, G. J. Mirjam Groenewold, Aneta Zegar, Katarzyna Owczarek, Sanjata Joshi, Mohamed Koukni, Philippe Arzel, Hugo Klaassen, Jean-Christophe Vanherck, Ilse Vandecaetsbeek, Niels Cremers, Kim Donckers, Thibault Francken, Tina Van Buyten, Jasper Rymenants, Joost Schepers, Krzysztof Pyrc, Rolf Hilgenfeld, Jean Dubuisson, Berend-Jan Bosch, Frank Van Kuppeveld, Cecilia Eydoux, Etienne Decroly, Bruno Canard, Lieve Naesens, Birgit Weynand, Eric J. Snijder, Sandrine Belouzard, Toshiyuki Shimizu, Ralf Bartenschlager, Daniel L. Hurdiss, Arnaud Marchand, Patrick Chaltin, Johan Neyts |
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| 245 | 1 | 2 | |a A coronavirus assembly inhibitor that targets the viral membrane protein |c Manon Laporte, Dirk Jochmans, Dorothée Bardiot, Lowiese Desmarets, Oliver J. Debski-Antoniak, Giulia Mizzon, Rana Abdelnabi, Pieter Leyssen, Winston Chiu, Zhikuan Zhang, Norimichi Nomura, Sandro Boland, Umeharu Ohto, Yannick Stahl, Jurgen Wuyts, Steven De Jonghe, Annelies Stevaert, Martijn J. van Hemert, Brenda W. Bontes, Patrick Wanningen, G. J. Mirjam Groenewold, Aneta Zegar, Katarzyna Owczarek, Sanjata Joshi, Mohamed Koukni, Philippe Arzel, Hugo Klaassen, Jean-Christophe Vanherck, Ilse Vandecaetsbeek, Niels Cremers, Kim Donckers, Thibault Francken, Tina Van Buyten, Jasper Rymenants, Joost Schepers, Krzysztof Pyrc, Rolf Hilgenfeld, Jean Dubuisson, Berend-Jan Bosch, Frank Van Kuppeveld, Cecilia Eydoux, Etienne Decroly, Bruno Canard, Lieve Naesens, Birgit Weynand, Eric J. Snijder, Sandrine Belouzard, Toshiyuki Shimizu, Ralf Bartenschlager, Daniel L. Hurdiss, Arnaud Marchand, Patrick Chaltin, Johan Neyts |
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| 520 | |a The coronavirus membrane protein (M) is the main organizer of coronavirus assembly1-3. 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. | ||
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