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<p>Nipah (NiV) and Hendra (HeV) viruses pose a serious threat, causing global outbreaks with high fatality rates. The fusion (F) glycoprotein, located on the viral surface, presents a conserved and promising neutralizing target. Here, we identify two C-type nanoantibodies (C-Nabs), 1A1-3-22 and 2A1-3-8, targeting F protein. 2A1-3-8 exhibits cross-reactivity against both viruses, whereas 1A1-3-22 shows specificity to NiV. The half-life-extended 2A1-3-8 provides 100% protection against NiV lethal challenge in female hamsters. Cryo-EM analysis reveals that 1A1-3-22 and 2A1-3-8 target similar funnel-like epitopes. Based on the unique “cavity-filling” mechanism, we engineered 2A1-3-8 to exhibit enhanced neutralizing activity and converted 1A1-3-22 from a NiV-specific antibody into a broad-spectrum one. In addition, the affinity-matured 2A1-3-8 clones exhibit broad binding activity against F proteins spanning both the <i>Henipavirus</i> and <i>Parahenipavirus</i> genera. Our study not only demonstrates the potential of C-Nabs for clinical application against henipaviruses, but also provides critical epitope information for the future design and engineering of antibodies and the development of other antivirals.</p>

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Highly potent C-type nanoantibodies neutralize Nipah and Hendra viruses by cavity filling on fusion glycoprotein

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Shengdong Wang,
  • Guibo Rao,
  • Xinghai Zhang,
  • Yanfeng Yao,
  • Li Chen,
  • Shaohong Chen,
  • Haiwei Zhang,
  • Hang Liu,
  • Miaoyu Chen,
  • Wujian Li,
  • Sheng Cao,
  • Sandra Chiu,
  • Rui Gong

摘要

Nipah (NiV) and Hendra (HeV) viruses pose a serious threat, causing global outbreaks with high fatality rates. The fusion (F) glycoprotein, located on the viral surface, presents a conserved and promising neutralizing target. Here, we identify two C-type nanoantibodies (C-Nabs), 1A1-3-22 and 2A1-3-8, targeting F protein. 2A1-3-8 exhibits cross-reactivity against both viruses, whereas 1A1-3-22 shows specificity to NiV. The half-life-extended 2A1-3-8 provides 100% protection against NiV lethal challenge in female hamsters. Cryo-EM analysis reveals that 1A1-3-22 and 2A1-3-8 target similar funnel-like epitopes. Based on the unique “cavity-filling” mechanism, we engineered 2A1-3-8 to exhibit enhanced neutralizing activity and converted 1A1-3-22 from a NiV-specific antibody into a broad-spectrum one. In addition, the affinity-matured 2A1-3-8 clones exhibit broad binding activity against F proteins spanning both the Henipavirus and Parahenipavirus genera. Our study not only demonstrates the potential of C-Nabs for clinical application against henipaviruses, but also provides critical epitope information for the future design and engineering of antibodies and the development of other antivirals.