Laporte Manon, Jochmans Dirk, Bardiot Dorothée, Desmarets Lowiese, Debski-Antoniak Oliver J, Mizzon Giulia, Abdelnabi Rana, Leyssen Pieter, Chiu Winston, Zhang Zhikuan, Nomura Norimichi, Boland Sandro, Ohto Umeharu, Stahl Yannick, Wuyts Jurgen, De Jonghe Steven, Stevaert Annelies, van Hemert Martijn J, Bontes Brenda W, Wanningen Patrick, Groenewold G J Mirjam, Zegar Aneta, Owczarek Katarzyna, Joshi Sanjata, Koukni Mohamed, Arzel Philippe, Klaassen Hugo, Vanherck Jean-Christophe, Vandecaetsbeek Ilse, Cremers Niels, Donckers Kim, Francken Thibault, Van Buyten Tina, Rymenants Jasper, Schepers Joost, Pyrc Krzysztof, Hilgenfeld Rolf, Dubuisson Jean, Bosch Berend-Jan, Van Kuppeveld Frank, Eydoux Cecilia, Decroly Etienne, Canard Bruno, Naesens Lieve, Weynand Birgit, Snijder Eric J, Belouzard Sandrine, Shimizu Toshiyuki, Bartenschlager Ralf, Hurdiss Daniel L, Marchand Arnaud, Chaltin Patrick, Neyts Johan
Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
CISTIM Leuven vzw, Leuven, Belgium.
Nature. 2025 Apr;640(8058):514-523. doi: 10.1038/s41586-025-08773-x. Epub 2025 Mar 26.
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.
冠状病毒膜蛋白（M）是冠状病毒组装的主要组织者。在此，我们报告了一种靶向M的分子CIM - 834，它能阻断严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的组装。CIM - 834是通过高通量表型抗病毒筛选，随后进行药物化学研究和靶点鉴定而获得的。CIM - 834可抑制SARS-CoV-2（包括多种变体）和严重急性呼吸综合征冠状病毒（SARS-CoV）的复制。在经鼻感染SARS-CoV-2的重症联合免疫缺陷（SCID）小鼠和叙利亚仓鼠中，口服治疗可将肺部病毒滴度降低至几乎检测不到的水平，即使（如在小鼠中所示）治疗延迟至终点前24小时。对感染的仓鼠进行治疗可防止病毒传播给未治疗的哨兵动物。透射电子显微镜研究表明，用CIM - 834处理的细胞中完全不存在病毒粒子组装。单颗粒冷冻电子显微镜显示，CIM - 834以其短形式结合并稳定M蛋白，从而阻止其向成功组装病毒粒子所需的长形式的构象转换。总之，我们在冠状病毒复制周期中发现了一个新的可成药靶点以及一种能有效抑制它的小分子。
