Programmable antibody-based chimeric entry receptors for sarbecoviruses
Communications Biology, vol. 9
Abstract
Despite frequent spillover of sarbecoviruses, most SARS-related viruses discovered in animals fail to engage human ACE2 (hACE2), limiting mechanistic insight and risk assessment. Here we developed antibody-based chimeric entry receptors (ABCERs) that reprogram antibody-antigen recognition into a synthetic, cell-anchored receptor interface. By replacing the extracellular protease domain of hACE2 with single-chain variable fragments (scFvs) from broadly neutralizing antibodies, ABCERs mimic viral receptor engagement while preserving the intracellular architecture required for cathepsin L-dependent endocytic fusion. This modular design converts antibody specificity into a programmable entry module, supporting efficient infection and replication of diverse sarbecoviruses from both clinical and animal sources. Among the tested scFvs, E7 exhibited exceptional breadth, recognizing conserved epitopes shared across representative sarbecoviruses from all clades. Sera from Pfizer-BioNTech mRNA-vaccinated individuals potently blocked E7 binding to SARS-CoV-2 but showed limited cross-inhibition of E7 interactions with RBDs from hACE2-independent sarbecoviruses, revealing a substantial gap in current vaccine-induced humoral immunity. Together, our findings establish E7-based ABCERs as a programmable synthetic receptor platform that bridges antibody recognition and viral propagation, offering a universal tool for isolating, studying, and surveying sarbecoviruses beyond the hACE2-dependent paradigm.
Authors 13
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Duke-NUS Medical School · East China Normal University
Affiliation as printed
Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, China
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, China
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National Centre for Infectious Diseases
Affiliation as printed
National Centre for Infectious Diseases, Singapore, Singapore
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Affiliation as printed
Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Affiliation as printed
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
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Leyden Laboratories BV (Netherlands)
Affiliation as printed
Leyden Labs Asia, Singapore, Singapore
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Chulalongkorn University · Duke-NUS Medical School · MRC University of Glasgow Centre for Virus Research · The University of Tokyo · Kumamoto University
Affiliation as printed
Collaboration Unit for Infection, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan
Department of Pathology, Immunology and Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
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Affiliation as printed
Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
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Affiliation as printed
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
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National Centre for Infectious Diseases
Affiliation as printed
National Centre for Infectious Diseases, Singapore, Singapore
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National Centre for Infectious Diseases
Affiliation as printed
National Centre for Infectious Diseases, Singapore, Singapore
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Haifeng Ye corresponding
Affiliation as printed
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, China. hfye@bio.ecnu.edu.cn
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Lin‐Fa Wang corresponding
Duke-NUS Medical School · National Centre for Infectious Diseases
Affiliation as printed
National Centre for Infectious Diseases, Singapore, Singapore. linfa.wang@duke-nus.edu.sg
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore. linfa.wang@duke-nus.edu.sg
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Chee Wah Tan corresponding
National University of Singapore · Duke-NUS Medical School
Affiliation as printed
Infectious Diseases Translational Research Program, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. gmstanc@nus.edu.sg
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore. gmstanc@nus.edu.sg
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