Scholarlink

<p>Miniaturizing biologically complex structural motifs to produce synthetic functional mimetics holds significant promise for development of new therapeutic modalities. Here, we demonstrate a unique approach using the key binding loop of the single variable domain of a heavy chain (V<sub>H</sub>H) llama antibody as a starting point for peptide design. V<sub>H</sub>H antibodies of camelids and sharks generally have longer, but more ligand-efficient complementarity determining region 3 (CDR3) loops and are relatively stable structures. We harnessed these attributes as templates for design of a series of synthetic macrocyclic peptides. The designed peptides exhibit nanomolar binding to influenza hemagglutinin (HA) and heterosubtypic in vitro neutralization breadth against influenza A viruses by inhibiting the low pH mediated HA conformational changes that lead to membrane fusion. X-ray structures of peptide-HA complexes reveal high structural mimicry with the parent V<sub>H</sub>H antibody. One such macrocycle peptide candidate is promising for further development of broad protection against influenza A group 1 viruses.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

VHH antibody loop guides design of a synthetic macrocyclic peptide that potently blocks influenza virus membrane fusion

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月18日

查看全文
  • Rameshwar U. Kadam,
  • Jarek Juraszek,
  • Boerries Brandenburg,
  • Divita Garg,
  • Xueyong Zhu,
  • Mandy Jongeneelen,
  • Wim B. G. Schepens,
  • Bart Stoops,
  • Jan Vermond,
  • Wouter Goutier,
  • Chan Tang,
  • Sven Blokland,
  • Ronald Vogels,
  • Robert H. E. Friesen,
  • Maria J. P. van Dongen,
  • Ian A. Wilson

摘要

Miniaturizing biologically complex structural motifs to produce synthetic functional mimetics holds significant promise for development of new therapeutic modalities. Here, we demonstrate a unique approach using the key binding loop of the single variable domain of a heavy chain (VHH) llama antibody as a starting point for peptide design. VHH antibodies of camelids and sharks generally have longer, but more ligand-efficient complementarity determining region 3 (CDR3) loops and are relatively stable structures. We harnessed these attributes as templates for design of a series of synthetic macrocyclic peptides. The designed peptides exhibit nanomolar binding to influenza hemagglutinin (HA) and heterosubtypic in vitro neutralization breadth against influenza A viruses by inhibiting the low pH mediated HA conformational changes that lead to membrane fusion. X-ray structures of peptide-HA complexes reveal high structural mimicry with the parent VHH antibody. One such macrocycle peptide candidate is promising for further development of broad protection against influenza A group 1 viruses.