君威研究所Johan Neyts研究组取得一项新突破。他们揭示了一种针对病毒膜蛋白的冠状病毒组装抑制剂。该研究于2025年3月26日发表于国际一流学术期刊《自然》杂志上。

该课题组研究人员报道了一种M靶向分子CIM-834，它可以阻止SARS-CoV-2的组装。CIM-834是通过高通量表型抗病毒筛选、药物化学努力和靶点阐明获得的。CIM-834抑制SARS-CoV-2（包括广泛的变体）和SARS-CoV的复制。在SCID小鼠和经鼻感染SARS-CoV-2的叙利亚仓鼠中，口服治疗将肺部病毒滴度降低到几乎无法检测到的水平，即使（如小鼠所示）治疗延迟到24终点前的H。对受感染的仓鼠进行治疗可防止传染给未经治疗的仓鼠。透射电镜研究表明，用CIM-834处理的细胞完全不存在病毒粒子组装。单粒子冷冻电镜显示，CIM-834结合并稳定了M蛋白的短形态，从而阻止了M蛋白的构象转换为长形态，而长形态是成功的粒子组装所必需的。总之，研究人员在冠状病毒的复制周期中发现了一个新的可药物靶点和一个有效抑制它的小分子。

研究人员表示，冠状病毒膜蛋白(M)是冠状病毒组装的主要组织者。

附：英文原文

Title: A coronavirus assembly inhibitor that targets the viral membrane protein

Author: Laporte, Manon, Jochmans, Dirk, Bardiot, Dorothe, 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

Issue&Volume: 2025-03-26

Abstract: The coronavirus membrane protein (M) is the main organizer of coronavirus assembly1,2,3. 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 24h 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.

DOI: 10.1038/s41586-025-08773-x

Source: https://www.nature.com/articles/s41586-025-08773-x