A coronavirus assembly inhibitor that targets the viral membrane protein

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 Jonghe, Annelies Stevaert, Martijn J. 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 Buyten, Jasper Rymenants, Joost Schepers, Krzysztof Pyrc, Rolf Hilgenfeld, Jean Dubuisson, Berend-Jan Bosch, Frank 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 and Johan Neyts ()
Additional contact information
Manon Laporte: KU Leuven
Dirk Jochmans: KU Leuven
Dorothée Bardiot: CISTIM Leuven vzw
Lowiese Desmarets: Université de Lille
Oliver J. Debski-Antoniak: Utrecht University
Giulia Mizzon: University of Heidelberg
Rana Abdelnabi: KU Leuven
Pieter Leyssen: KU Leuven
Winston Chiu: KU Leuven
Zhikuan Zhang: University of Tokyo
Norimichi Nomura: Kyoto University
Sandro Boland: CISTIM Leuven vzw
Umeharu Ohto: University of Tokyo
Yannick Stahl: University of Heidelberg
Jurgen Wuyts: CISTIM Leuven vzw
Steven Jonghe: KU Leuven
Annelies Stevaert: KU Leuven
Martijn J. Hemert: Leiden University Medical Center
Brenda W. Bontes: Leiden University Medical Center
Patrick Wanningen: Leiden University Medical Center
G. J. Mirjam Groenewold: Leiden University Medical Center
Aneta Zegar: Jagiellonian University
Katarzyna Owczarek: Jagiellonian University
Sanjata Joshi: University of Lübeck
Mohamed Koukni: CISTIM Leuven vzw
Philippe Arzel: CISTIM Leuven vzw
Hugo Klaassen: CISTIM Leuven vzw
Jean-Christophe Vanherck: CISTIM Leuven vzw
Ilse Vandecaetsbeek: CISTIM Leuven vzw
Niels Cremers: KU Leuven
Kim Donckers: KU Leuven
Thibault Francken: KU Leuven
Tina Buyten: KU Leuven
Jasper Rymenants: KU Leuven
Joost Schepers: KU Leuven
Krzysztof Pyrc: Jagiellonian University
Rolf Hilgenfeld: University of Lübeck
Jean Dubuisson: Université de Lille
Berend-Jan Bosch: Utrecht University
Frank Kuppeveld: Utrecht University
Cecilia Eydoux: Aix-Marseille Univ., CNRS, Faculté des Sciences Campus Luminy
Etienne Decroly: Aix-Marseille Univ., CNRS, Faculté des Sciences Campus Luminy
Bruno Canard: Aix-Marseille Univ., CNRS, Faculté des Sciences Campus Luminy
Lieve Naesens: KU Leuven
Birgit Weynand: KU Leuven
Eric J. Snijder: Leiden University Medical Center
Sandrine Belouzard: Université de Lille
Toshiyuki Shimizu: University of Tokyo
Ralf Bartenschlager: University of Heidelberg
Daniel L. Hurdiss: Utrecht University
Arnaud Marchand: CISTIM Leuven vzw
Patrick Chaltin: CISTIM Leuven vzw
Johan Neyts: KU Leuven

Nature, 2025, vol. 640, issue 8058, 514-523

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08773-x

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