Early fusion intermediate of ACE2-using coronavirus spike acting as antiviral target

Published: 22 January 2025| Version 1 | DOI: 10.17632/7t9snvwv3p.1
Contributors:
Lixiao Xing, Zhimin Liu, Xinling Wang, Qianying Liu, Wei Xu, Qiyu Mao, Xiang Zhang, Aihua Hao, Shuai Xia, Zezhong Liu, Lujia Sun, Guangxu Zhang, Qian Wang, Zhenguo Chen, Shibo Jiang, Lei Sun, Lu Lu

Description

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 ACE2-induced early fusion intermediate conformation (E-FIC) of SARS-CoV-2 spike in which HR1 in S2 has ejected while S1 remains attached. This E-FIC can transition to the late fusion intermediate conformation 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 target for the development of a dual-functional antiviral for the prevention and treatment of ACE2-using coronavirus infection.

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Institutions

  • Fudan University

Categories

Membrane Fusion, Viral Entry, Antiviral Agent Active against Respiratory Viruses, Coronavirus

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