利用血管紧张素转换酶2的冠状病毒刺突蛋白早期融合中间体作为抗病毒靶点。
Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target.
作者信息
Xing Lixiao, Liu Zhimin, Wang Xinling, Liu Qianying, Xu Wei, Mao Qiyu, Zhang Xiang, Hao Aihua, Xia Shuai, Liu Zezhong, Sun Lujia, Zhang Guangxu, Wang Qian, Chen Zhenguo, Jiang Shibo, Sun Lei, Lu Lu
机构信息
Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Fifth People's Hospital, Institutes of Biomedical Sciences, Shanghai Public Health Clinical Center, Shanghai Medical College, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China.
Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Fifth People's Hospital, Institutes of Biomedical Sciences, Shanghai Public Health Clinical Center, Shanghai Medical College, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China; School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan, China.
出版信息
Cell. 2025 Mar 6;188(5):1297-1314.e24. doi: 10.1016/j.cell.2025.01.012. Epub 2025 Jan 30.
Coronavirus fusion with and entry into the host cell depends on viral spike, which acts as a crucial component of viral infection. However, the lack of receptor-activated spike intermediate conformation has hindered a comprehensive understanding of spike-induced membrane fusion. Here, we captured an angiotensin-converting enzyme 2 (ACE2)-induced early fusion intermediate conformation (E-FIC) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike in which heptad repeat 1 (HR1) in S2 has ejected while S1 remains attached. This E-FIC can transition to the late FIC after S2' cleavage. Leveraging this discovery, we designed an E-FIC-targeted dual-functional antiviral protein, AL5E. AL5E effectively inactivated ACE2-using coronaviruses and inhibited their infection, outperforming a mono-functional antiviral in protecting animals against these coronaviruses. This study has identified the E-FIC and used it as a target for the development of a dual-functional antiviral for the prevention and treatment of ACE2-using coronavirus infection.
冠状病毒与宿主细胞的融合及进入依赖于病毒刺突蛋白，它是病毒感染的关键组成部分。然而，缺乏受体激活的刺突中间构象阻碍了对刺突诱导的膜融合的全面理解。在此，我们捕获了严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的血管紧张素转换酶2（ACE2）诱导的早期融合中间构象（E-FIC），其中S2中的七肽重复序列1（HR1）已弹出，而S1仍附着。这种E-FIC在S2'切割后可转变为晚期FIC。利用这一发现，我们设计了一种靶向E-FIC的双功能抗病毒蛋白AL5E。AL5E有效灭活了利用ACE2的冠状病毒并抑制其感染，在保护动物免受这些冠状病毒感染方面优于单功能抗病毒药物。这项研究确定了E-FIC，并将其用作开发预防和治疗利用ACE2的冠状病毒感染的双功能抗病毒药物的靶点。
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