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Cell . 2 Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target

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  • Cell . 2 Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target

    Cell


    . 2025 Jan 24:S0092-8674(25)00041-8.
    doi: 10.1016/j.cell.2025.01.012. Online ahead of print. Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target

    Lixiao Xing 1 , Zhimin Liu 1 , Xinling Wang 1 , Qianying Liu 2 , Wei Xu 1 , Qiyu Mao 1 , Xiang Zhang 1 , Aihua Hao 1 , Shuai Xia 1 , Zezhong Liu 3 , Lujia Sun 1 , Guangxu Zhang 1 , Qian Wang 1 , Zhenguo Chen 1 , Shibo Jiang 4 , Lei Sun 5 , Lu Lu 6



    AffiliationsAbstract

    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.

    Keywords: coronavirus; dual-functional antivirals; early fusion intermediate conformation; membrane fusion mechanism; spike.

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