Van Damme Ellen, Abeywickrema Pravien, Yin Yanting, Xie Jiexiong, Jacobs Sofie, Mann Mandeep Kaur, Doijen Jordi, Miller Robyn, Piassek Madison, Marsili Simone, Subramanian Murali, Gottlieb Leah, Abdelnabi Rana, Van Gool Michiel, Van den Broeck Nick, De Pauw Ines, Diels Annick, Vermeulen Peter, Temmerman Koen, Scobey Trevor, Mattocks Melissa, Schäfer Alexandra, Jochmans Dirk, De Jonghe Steven, Leyssen Pieter, Chiu Winston, Diosa Toro Mayra, Zwaagstra Marleen, Leijs Anouk A, De Gruyter Heidi L M, Buyck Christophe, Van Den Heede Klaas, Jacobs Frank, Van den Eynde Christel, Thijs Laura, Raeymaekers Valerie, Miller Seth, Del Rosario Amanda, Neyts Johan, Peeters Danielle, Baric Ralph S, van Kuppeveld Frank J M, Snijder Eric J, van Hemert Martijn J, Monshouwer Mario, Sharma Sujata, Draghia-Akli Ruxandra, Koul Anil, Van Loock Marnix
Global Public Health R&D, Janssen Pharmaceutica, Beerse, Belgium.
Discovery Technologies & Molecular Pharmacology, Janssen Research & Development, Spring House, PA, USA.
Nature. 2025 Apr;640(8058):506-513. doi: 10.1038/s41586-025-08651-6. Epub 2025 Mar 26.
The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log-transformed RNA copies and 50% tissue culture infective dose (TCID) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.
β冠状病毒的膜（M）蛋白高度保守，在病毒组装中起关键作用。在此，我们描述了一种靶向冠状病毒M蛋白的小分子抑制剂JNJ-9676的鉴定。JNJ-9676在体外对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）、SARS-CoV以及源自蝙蝠和穿山甲的人畜共患起源的沙贝病毒株具有纳摩尔级抗病毒活性。利用低温电子显微镜（cryo-EM），我们确定了由M蛋白二聚体的跨膜结构域形成的JNJ-9676结合口袋。化合物结合使M蛋白二聚体稳定在其长形式和短形式之间的改变构象状态，从而阻止传染性病毒的释放。在暴露前的叙利亚金黄地鼠模型中，JNJ-9676（25毫克/千克，每天两次）显示出优异的疗效，表现为肺部病毒载量和传染性病毒显著降低，分别减少了3.5和4个对数转换的RNA拷贝以及每毫克肺组织50%组织培养感染剂量（TCID）。该剂量下的组织病理学评分降至基线水平。在暴露后的地鼠模型中，即使在感染后48小时（此时观察到病毒载量峰值）添加JNJ-9676，其在75毫克/千克、每天两次时仍有效。M蛋白是阻断冠状病毒复制的一个有吸引力的抗病毒靶点，而JNJ-9676代表了一个有趣的化学系列，有助于鉴定应对当前和未来冠状病毒大流行的临床候选药物。
