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 () and Yanling Wu ()
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Yulu Wang: Fudan University
Yifang Sun: Fudan University
Zhaoling Shen: Fudan University
Cong Wang: Fudan University
Jun Qian: Fudan University
Qiyu Mao: Fudan University
Yajie Wang: Fudan University
Wenping Song: Fudan University
Yu Kong: Fudan University
Changyou Zhan: Fudan University
Zhenguo Chen: Fudan University
Dimiter S. Dimitrov: University of Pittsburgh Department of Medicine
Zhenlin Yang: Fudan University
Shibo Jiang: Fudan University
Fan Wu: Fudan University
Lu Lu: Fudan University
Tianlei Ying: Fudan University
Lei Sun: Fudan University
Yanling Wu: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51066-6

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