2025/03/26 by Manon Laporte, Dirk Jochmans, Dorothée Bardiot +50 · 1 voice · 1 citation
Medicine · Agricultural and Biological Sciences · #SARS-CoV-2 and COVID-19 Research #Viral gastroenteritis research and epidemiology #Animal Virus Infections Studies
paper · pdf · doi:10.1038/s41586-025-08773-x
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. High-throughput screening and hit optimization have led to the development of a small molecule, CIM-834, that targets the SARS-CoV-2 membrane protein and blocks assembly of the virus.