Design of customized coronavirus receptors

Peng Liu, Mei-Ling Huang, Hua Guo, Matthew McCallum, Jun-Yu Si, Yuan-Mei Chen, Chun-Li Wang, Xiao Yu, Lu-Lu Shi, Qing Xiong, Cheng-Bao Ma, John E. Bowen, Fei Tong, Chen Liu, Ye-hui Sun, Xiao Yang, Jing Chen, Ming Guo, Jing Li, Davide Corti, David Veesler (), Zheng-Li Shi () and Huan Yan ()
Additional contact information
Peng Liu: Wuhan University
Mei-Ling Huang: Wuhan University
Hua Guo: Chinese Academy of Sciences
Matthew McCallum: University of Washington
Jun-Yu Si: Wuhan University
Yuan-Mei Chen: Wuhan University
Chun-Li Wang: Wuhan University
Xiao Yu: Wuhan University
Lu-Lu Shi: Wuhan University
Qing Xiong: Wuhan University
Cheng-Bao Ma: Wuhan University
John E. Bowen: University of Washington
Fei Tong: Wuhan University
Chen Liu: Wuhan University
Ye-hui Sun: Wuhan University
Xiao Yang: Wuhan University
Jing Chen: Chinese Academy of Sciences
Ming Guo: Wuhan University
Jing Li: Wuhan University
Davide Corti: subsidiary of Vir Biotechnology
David Veesler: University of Washington
Zheng-Li Shi: Chinese Academy of Sciences
Huan Yan: Wuhan University

Nature, 2024, vol. 635, issue 8040, 978-986

Abstract: Abstract Although coronaviruses use diverse receptors, the characterization of coronaviruses with unknown receptors has been impeded by a lack of infection models1,2. Here we introduce a strategy to engineer functional customized viral receptors (CVRs). The modular design relies on building artificial receptor scaffolds comprising various modules and generating specific virus-binding domains. We identify key factors for CVRs to functionally mimic native receptors by facilitating spike proteolytic cleavage, membrane fusion, pseudovirus entry and propagation for various coronaviruses. We delineate functional SARS-CoV-2 spike receptor-binding sites for CVR design and reveal the mechanism of cell entry promoted by the N-terminal domain-targeting S2L20-CVR. We generated CVR-expressing cells for 12 representative coronaviruses from 6 subgenera, most of which lack known receptors, and show that a pan-sarbecovirus CVR supports propagation of a propagation-competent HKU3 pseudovirus and of authentic RsHuB2019A3. Using an HKU5-specific CVR, we successfully rescued wild-type and ZsGreen-HiBiT-incorporated HKU5-1 (LMH03f) and isolated a HKU5 strain from bat samples. Our study demonstrates the potential of the CVR strategy for establishing native receptor-independent infection models, providing a tool for studying viruses that lack known susceptible target cells.

Date: 2024
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DOI: 10.1038/s41586-024-08121-5

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