tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Zhimin Liu[SUP] 1 [/SUP], Xinling Wang[SUP] 1 [/SUP], Qianying Liu[SUP] 2 [/SUP], Wei Xu[SUP] 1 [/SUP], Qiyu Mao[SUP] 1 [/SUP], Xiang Zhang[SUP] 1 [/SUP], Aihua Hao[SUP] 1 [/SUP], Shuai Xia[SUP] 1 [/SUP], Zezhong Liu[SUP] 3 [/SUP], Lujia Sun[SUP] 1 [/SUP], Guangxu Zhang[SUP] 1 [/SUP], Qian Wang[SUP] 1 [/SUP], Zhenguo Chen[SUP] 1 [/SUP], Shibo Jiang[SUP] 4 [/SUP], Lei Sun[SUP] 5 [/SUP], Lu Lu[SUP] 6 [/SUP]
Affiliations
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.
. 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[SUP] 1 [/SUP], Zhimin Liu[SUP] 1 [/SUP], Xinling Wang[SUP] 1 [/SUP], Qianying Liu[SUP] 2 [/SUP], Wei Xu[SUP] 1 [/SUP], Qiyu Mao[SUP] 1 [/SUP], Xiang Zhang[SUP] 1 [/SUP], Aihua Hao[SUP] 1 [/SUP], Shuai Xia[SUP] 1 [/SUP], Zezhong Liu[SUP] 3 [/SUP], Lujia Sun[SUP] 1 [/SUP], Guangxu Zhang[SUP] 1 [/SUP], Qian Wang[SUP] 1 [/SUP], Zhenguo Chen[SUP] 1 [/SUP], Shibo Jiang[SUP] 4 [/SUP], Lei Sun[SUP] 5 [/SUP], Lu Lu[SUP] 6 [/SUP]
Affiliations
- PMID: 39889696
- DOI: 10.1016/j.cell.2025.01.012
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.