A coronavirus assembly inhibitor that targets the viral membrane protein

The coronavirus membrane protein (M) is the main organizer of coronavirus assembly<sup>1-3</sup>. 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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Publication Details

Journal
Nature
Published
2025-03-26
DOI
https://doi.org/10.1038/s41586-025-08773-x
Citations
19
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
29.32
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article

A coronavirus assembly inhibitor that targets the viral membrane protein

Ilse Vandecaetsbeek, Eric J. Snijder, Sandro Boland, Toshiyuki Shimizu et al.
19 citations
Nature
SARS-CoV-2 and COVID-19 Research
29.32
article

A coronavirus assembly inhibitor that targets the viral membrane protein

Ilse Vandecaetsbeek, Eric J. Snijder, Sandro Boland, Toshiyuki Shimizu, Ralf F. W. Bartenschlager, Zhikuan Zhang, Cécilia Eydoux, Jasper Rymenants, Patrick Chaltin, Kim Donckers, Oliver Debski-Antoniak, Dorothée Bardiot, Steven De Jonghe, Daniel L. Hurdiss, Sandrine Belouzard, Aneta Zegar, Lowiese Desmarets, Pieter Leyssen, Birgit Weynand, Bruno Canard, Frank J. M. van Kuppeveld, Arnaud Marchand, Rolf Hilgenfeld, S. Joshi, Niels Cremers, Hugo Klaassen, Giulia Mizzon, G. J. Mirjam Groenewold, Yannick Stahl, Umeharu Ohto, Annelies Stevaert, Philippe Arzel, Joost Schepers, Rana Abdelnabi, Jean‐Christophe Vanherck, Krzysztof Pyrć, Katarzyna Owczarek, Patrick Wanningen, Étienne Decroly, Thibault Francken, Norimichi Nomura, Dirk Jochmans, Martijn J. van Hemert, Winston Chiu, Berend‐Jan Bosch, Lieve M. J. Naesens, Tina Van Buyten, Brenda W. Bontes, Jean Dubuisson, Johan Neyts, Manon Laporte, Mohamed Koukni, Jurgen Wuyts
article en
19 citations

Abstract

The coronavirus membrane protein (M) is the main organizer of coronavirus assembly<sup>1-3</sup>. 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.

NatureVol. 640(8058)
Jagiellonian University (PL), Centre National de la Recherche Scientifique (FR), Inserm (FR), German Cancer Research Center (DE), Utrecht University (NL), Aix-Marseille Université (FR), Kyoto University (JP), Heidelberg University (DE), Université de Lille (FR), Rega Institute for Medical Research (BE), Leiden University Medical Center (NL), Institut Pasteur de Lille (FR), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire de Lille (FR), Center for Infection and Immunity of Lille (FR), German Center for Infection Research (DE), Architecture et Fonction des Macromolécules Biologiques (FR), The University of Tokyo (JP), University of Lübeck (DE), KU Leuven (BE)
Openalex Percentile: Top 0%
SARS-CoV-2 and COVID-19 Research
29.32
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