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TitleA coronavirus assembly inhibitor that targets the viral membrane protein.
Journal, issue, pagesNature, Vol. 640, Issue 8058, Page 514-523, Year 2025
Publish dateMar 26, 2025
AuthorsManon 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 /
PubMed AbstractThe coronavirus membrane protein (M) is the main organizer of coronavirus assembly. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained ...The coronavirus membrane protein (M) is the main organizer of coronavirus assembly. 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.
External linksNature / PubMed:40140569 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.3 Å
Structure data

EMDB-50034, PDB-9exa:
SARS-CoV-2 M protein dimer (short form) in complex with Fab-B and CIM-834
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-50035: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and incubated with CIM-834
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

PDB-1h7w:
Dihydropyrimidine dehydrogenase (DPD) from pig

Source
  • severe acute respiratory syndrome coronavirus 2
  • mus musculus (house mouse)
KeywordsVIRAL PROTEIN / Inhibitor / Complex / Membrane protein / Antibody

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