首页|Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain

Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain

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Almost all the neutralizing antibodies targeting the receptor-binding domain(RBD)of spike(S)protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged or emerging variants,such as Omicron and its sub-variants.This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies.Here,we present one nanobody,N235,displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants,including the newly emerged Omicron and its sub-variants.Cryo-electron microscopy demonstrates N235 binds a novel,conserved,cryptic epitope in the N-terminal domain(NTD)of the S protein,which interferes with the RBD in the neighboring S protein.The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex.Furthermore,a nano-IgM construct(MN235),engineered by fusing N235 with the human IgM Fc region,displays prevention via inducing S1 shedding and cross-linking virus particles.Compared to N235,MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro.The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo,suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.

Bo Liu、Honghui Liu、Pu Han、Xiaoyun Wang、Chunmei Wang、Xinxin Yan、Wenwen Lei、Ke Xu、Jianjie Zhou、Jianxun Qi、Ruiwen Fan、Guizhen Wu、Wen-xia Tian、George F.Gao、Qihui Wang

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College of Veterinary Medicine,Shanxi Agricultural University,030801 Jinzhong,China

CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences(CAS),100101 Beijing,China

School of Life Sciences,Yunnan University,650504 Kunming,Yunnan Province,China

NHC Key Laboratory of Biosafety,National Institute for Viral Disease Control and Prevention,Chinese Center for Disease Control and Prevention(China CDC),102206 Beijing,China

Savaid Medical School,University of Chinese Academy of Sciences,101408 Beijing,China

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National Key R&D Program of ChinaNational Science Fund for Distinguished Young ScholarsYoung Scientists In Basic Research

2022YFC230340382225021YSBR-010

2024

10.1038/s41392-024-01847-8

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

CSTPCD
ISSN：
年,卷(期)：2024.9(6)