A coronavirus assembly inhibitor that targets the viral membrane protein PMID: 40140569

ADC Targets in Oncology

2026-04-10

A coronavirus assembly inhibitor that targets the viral membrane protein

Nature. 2025 Apr;640(8058):514-523. doi: 10.1038/s41586-025-08773-x.

Manon Laporte ^# ¹ , Dirk Jochmans ^# ¹ , Dorothée Bardiot ² , Lowiese Desmarets ³ , Oliver J Debski-Antoniak ⁴ , Giulia Mizzon ⁵ ⁶ , Rana Abdelnabi ¹ ⁷ , Pieter Leyssen ¹ , Winston Chiu ¹ , Zhikuan Zhang ⁸ , Norimichi Nomura ⁹ , Sandro Boland ² , Umeharu Ohto ⁸ , Yannick Stahl ⁵ , Jurgen Wuyts ² , Steven De Jonghe ¹⁰ , Annelies Stevaert ¹⁰ , Martijn J van Hemert ¹¹ , Brenda W Bontes ¹¹ , Patrick Wanningen ¹¹ , G J Mirjam Groenewold ¹¹ , Aneta Zegar ¹² , Katarzyna Owczarek ¹² , Sanjata Joshi ¹³ , Mohamed Koukni ² , Philippe Arzel ² , Hugo Klaassen ² , Jean-Christophe Vanherck ² , Ilse Vandecaetsbeek ² , Niels Cremers ¹ , Kim Donckers ¹ , Thibault Francken ¹ , Tina Van Buyten ¹ , Jasper Rymenants ¹ , Joost Schepers ¹ , Krzysztof Pyrc ¹² , Rolf Hilgenfeld ¹³ , Jean Dubuisson ³ , Berend-Jan Bosch ⁴ , Frank Van Kuppeveld ⁴ , Cecilia Eydoux ¹⁴ , Etienne Decroly ¹⁴ , Bruno Canard ¹⁴ , Lieve Naesens ¹⁰ , Birgit Weynand ¹⁵ , Eric J Snijder ¹¹ , Sandrine Belouzard ³ , Toshiyuki Shimizu ⁸ , Ralf Bartenschlager ⁵ ⁶ ¹⁶ , Daniel L Hurdiss ⁴ , Arnaud Marchand ² , Patrick Chaltin ² ¹⁷ , Johan Neyts ¹⁸

Affiliations

1. Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
2. CISTIM Leuven vzw, Leuven, Belgium.
3. CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Université de Lille, Lille, France.
4. Virology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
5. Department of Infectious Diseases, Molecular Virology, Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany.
6. German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany.
7. Department of Microbiology, Immunology and Transplantation, VirusBank Platform, KU Leuven, Leuven, Belgium.
8. Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
9. Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
10. Structural and Translational Virology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
11. Molecular Virology Laboratory, Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
12. Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
13. Institute of Molecular Medicine and German Center for Infection Research (DZIF), University of Lübeck, Lübeck, Germany.
14. Architecture et Fonction des Macromolécules Biologiques (AFMB), Aix-Marseille Univ., CNRS, Faculté des Sciences Campus Luminy, Marseille, France.
15. Department of Imaging and Pathology, Division of Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
16. German Cancer Research Center (DKFZ), Heidelberg, Germany.
17. Centre for Drug Design and Discovery (CD3), KU Leuven, Leuven, Belgium.
18. Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium. [email protected].
# Contributed equally.

Abstract

The coronavirus membrane protein (M) is the main organizer of coronavirus assembly^1-3. 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.