Fully human single-domain antibody targeting a highly conserved cryptic epitope on the Nipah virus G protein

Yulu Wang; Yifang Sun; Zhaoling Shen; Cong Wang; Jun Qian; Qiyu Mao; Yajie Wang; Wenping Song; Yu Kong; Changyou Zhan; Zhenguo Chen; Dimiter S. Dimitrov; Zhenlin Yang; Shibo Jiang; Fan Wu; Lu Lu; Tianlei Ying; Lei Sun; Yanling Wu

doi:10.1038/s41467-024-51066-6

Nature Communications (Aug 2024)

Fully human single-domain antibody targeting a highly conserved cryptic epitope on the Nipah virus G protein

Yulu Wang,
Yifang Sun,
Zhaoling Shen,
Cong Wang,
Jun Qian,
Qiyu Mao,
Yajie Wang,
Wenping Song,
Yu Kong,
Changyou Zhan,
Zhenguo Chen,
Dimiter S. Dimitrov,
Zhenlin Yang,
Shibo Jiang,
Fan Wu,
Lu Lu,
Tianlei Ying,
Lei Sun,
Yanling Wu

Affiliations

Yulu Wang: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Yifang Sun: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Zhaoling Shen: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Cong Wang: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Jun Qian: Key Laboratory of Smart Drug Delivery (MOE), School of Pharmacy, Fudan University
Qiyu Mao: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Yajie Wang: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Wenping Song: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Yu Kong: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Changyou Zhan: Department of Pharmacology, School of Basic Medical Sciences & Center of Medical Research and Innovation, Shanghai Pudong Hospital & State Key Laboratory of Molecular Engineering of Polymers, Fudan University
Zhenguo Chen: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Dimiter S. Dimitrov: University of Pittsburgh Department of Medicine
Zhenlin Yang: Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University
Shibo Jiang: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Fan Wu: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Lu Lu: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Tianlei Ying: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Lei Sun: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University
Yanling Wu: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University

DOI: https://doi.org/10.1038/s41467-024-51066-6
Journal volume & issue: Vol. 15, no. 1
pp. 1 – 13

Abstract

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Abstract Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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