tetano
Editor, Senior Moderator
Nature
. 2025 Mar 26.
doi: 10.1038/s41586-025-08773-x. Online ahead of print. A coronavirus assembly inhibitor that targets the viral membrane protein
Manon Laporte[SUP] #[/SUP][SUP] 1 [/SUP], Dirk Jochmans[SUP] #[/SUP][SUP] 1 [/SUP], Dorothée Bardiot[SUP] 2 [/SUP], Lowiese Desmarets[SUP] 3 [/SUP], Oliver J Debski-Antoniak[SUP] 4 [/SUP], Giulia Mizzon[SUP] 5 6 [/SUP], Rana Abdelnabi[SUP] 1 7 [/SUP], Pieter Leyssen[SUP] 1 [/SUP], Winston Chiu[SUP] 1 [/SUP], Zhikuan Zhang[SUP] 8 [/SUP], Norimichi Nomura[SUP] 9 [/SUP], Sandro Boland[SUP] 2 [/SUP], Umeharu Ohto[SUP] 8 [/SUP], Yannick Stahl[SUP] 5 [/SUP], Jurgen Wuyts[SUP] 2 [/SUP], Steven De Jonghe[SUP] 10 [/SUP], Annelies Stevaert[SUP] 10 [/SUP], Martijn J van Hemert[SUP] 11 [/SUP], Brenda W Bontes[SUP] 11 [/SUP], Patrick Wanningen[SUP] 11 [/SUP], G J Mirjam Groenewold[SUP] 11 [/SUP], Aneta Zegar[SUP] 12 [/SUP], Katarzyna Owczarek[SUP] 12 [/SUP], Sanjata Joshi[SUP] 13 [/SUP], Mohamed Koukni[SUP] 2 [/SUP], Philippe Arzel[SUP] 2 [/SUP], Hugo Klaassen[SUP] 2 [/SUP], Jean-Christophe Vanherck[SUP] 2 [/SUP], Ilse Vandecaetsbeek[SUP] 2 [/SUP], Niels Cremers[SUP] 1 [/SUP], Kim Donckers[SUP] 1 [/SUP], Thibault Francken[SUP] 1 [/SUP], Tina Van Buyten[SUP] 1 [/SUP], Jasper Rymenants[SUP] 1 [/SUP], Joost Schepers[SUP] 1 [/SUP], Krzysztof Pyrc[SUP] 12 [/SUP], Rolf Hilgenfeld[SUP] 13 [/SUP], Jean Dubuisson[SUP] 3 [/SUP], Berend-Jan Bosch[SUP] 4 [/SUP], Frank Van Kuppeveld[SUP] 4 [/SUP], Cecilia Eydoux[SUP] 14 [/SUP], Etienne Decroly[SUP] 14 [/SUP], Bruno Canard[SUP] 14 [/SUP], Lieve Naesens[SUP] 10 [/SUP], Birgit Weynand[SUP] 15 [/SUP], Eric J Snijder[SUP] 11 [/SUP], Sandrine Belouzard[SUP] 3 [/SUP], Toshiyuki Shimizu[SUP] 8 [/SUP], Ralf Bartenschlager[SUP] 5 6 16 [/SUP], Daniel L Hurdiss[SUP] 4 [/SUP], Arnaud Marchand[SUP] 2 [/SUP], Patrick Chaltin[SUP] 2 17 [/SUP], Johan Neyts[SUP] 18 [/SUP]
Affiliations
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.
. 2025 Mar 26.
doi: 10.1038/s41586-025-08773-x. Online ahead of print. A coronavirus assembly inhibitor that targets the viral membrane protein
Manon Laporte[SUP] #[/SUP][SUP] 1 [/SUP], Dirk Jochmans[SUP] #[/SUP][SUP] 1 [/SUP], Dorothée Bardiot[SUP] 2 [/SUP], Lowiese Desmarets[SUP] 3 [/SUP], Oliver J Debski-Antoniak[SUP] 4 [/SUP], Giulia Mizzon[SUP] 5 6 [/SUP], Rana Abdelnabi[SUP] 1 7 [/SUP], Pieter Leyssen[SUP] 1 [/SUP], Winston Chiu[SUP] 1 [/SUP], Zhikuan Zhang[SUP] 8 [/SUP], Norimichi Nomura[SUP] 9 [/SUP], Sandro Boland[SUP] 2 [/SUP], Umeharu Ohto[SUP] 8 [/SUP], Yannick Stahl[SUP] 5 [/SUP], Jurgen Wuyts[SUP] 2 [/SUP], Steven De Jonghe[SUP] 10 [/SUP], Annelies Stevaert[SUP] 10 [/SUP], Martijn J van Hemert[SUP] 11 [/SUP], Brenda W Bontes[SUP] 11 [/SUP], Patrick Wanningen[SUP] 11 [/SUP], G J Mirjam Groenewold[SUP] 11 [/SUP], Aneta Zegar[SUP] 12 [/SUP], Katarzyna Owczarek[SUP] 12 [/SUP], Sanjata Joshi[SUP] 13 [/SUP], Mohamed Koukni[SUP] 2 [/SUP], Philippe Arzel[SUP] 2 [/SUP], Hugo Klaassen[SUP] 2 [/SUP], Jean-Christophe Vanherck[SUP] 2 [/SUP], Ilse Vandecaetsbeek[SUP] 2 [/SUP], Niels Cremers[SUP] 1 [/SUP], Kim Donckers[SUP] 1 [/SUP], Thibault Francken[SUP] 1 [/SUP], Tina Van Buyten[SUP] 1 [/SUP], Jasper Rymenants[SUP] 1 [/SUP], Joost Schepers[SUP] 1 [/SUP], Krzysztof Pyrc[SUP] 12 [/SUP], Rolf Hilgenfeld[SUP] 13 [/SUP], Jean Dubuisson[SUP] 3 [/SUP], Berend-Jan Bosch[SUP] 4 [/SUP], Frank Van Kuppeveld[SUP] 4 [/SUP], Cecilia Eydoux[SUP] 14 [/SUP], Etienne Decroly[SUP] 14 [/SUP], Bruno Canard[SUP] 14 [/SUP], Lieve Naesens[SUP] 10 [/SUP], Birgit Weynand[SUP] 15 [/SUP], Eric J Snijder[SUP] 11 [/SUP], Sandrine Belouzard[SUP] 3 [/SUP], Toshiyuki Shimizu[SUP] 8 [/SUP], Ralf Bartenschlager[SUP] 5 6 16 [/SUP], Daniel L Hurdiss[SUP] 4 [/SUP], Arnaud Marchand[SUP] 2 [/SUP], Patrick Chaltin[SUP] 2 17 [/SUP], Johan Neyts[SUP] 18 [/SUP]
Affiliations
- PMID: 40140569
- DOI: 10.1038/s41586-025-08773-x
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.