tetano
Editor, Senior Moderator
Npj Viruses
. 2025 Dec 18;3(1):83.
doi: 10.1038/s44298-025-00166-1. V[SUB]H[/SUB]H antibody loop guides design of a synthetic macrocyclic peptide that potently blocks influenza virus membrane fusion
Rameshwar U Kadam[SUP] #[/SUP][SUP] 1 2 [/SUP], Jarek Juraszek[SUP] #[/SUP][SUP] 3 4 [/SUP], Boerries Brandenburg[SUP] 3 [/SUP], Divita Garg[SUP] 5 [/SUP], Xueyong Zhu[SUP] 5 [/SUP], Mandy Jongeneelen[SUP] 3 4 [/SUP], Wim B G Schepens[SUP] 6 [/SUP], Bart Stoops[SUP] 6 7 [/SUP], Jan Vermond[SUP] 3 [/SUP], Wouter Goutier[SUP] 3 [/SUP], Chan Tang[SUP] 3 [/SUP], Sven Blokland[SUP] 3 [/SUP], Ronald Vogels[SUP] 3 [/SUP], Robert H E Friesen[SUP] 3 4 [/SUP], Maria J P van Dongen[SUP] 3 6 8 [/SUP], Ian A Wilson[SUP] 9 10 [/SUP]
Affiliations
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.
. 2025 Dec 18;3(1):83.
doi: 10.1038/s44298-025-00166-1. V[SUB]H[/SUB]H antibody loop guides design of a synthetic macrocyclic peptide that potently blocks influenza virus membrane fusion
Rameshwar U Kadam[SUP] #[/SUP][SUP] 1 2 [/SUP], Jarek Juraszek[SUP] #[/SUP][SUP] 3 4 [/SUP], Boerries Brandenburg[SUP] 3 [/SUP], Divita Garg[SUP] 5 [/SUP], Xueyong Zhu[SUP] 5 [/SUP], Mandy Jongeneelen[SUP] 3 4 [/SUP], Wim B G Schepens[SUP] 6 [/SUP], Bart Stoops[SUP] 6 7 [/SUP], Jan Vermond[SUP] 3 [/SUP], Wouter Goutier[SUP] 3 [/SUP], Chan Tang[SUP] 3 [/SUP], Sven Blokland[SUP] 3 [/SUP], Ronald Vogels[SUP] 3 [/SUP], Robert H E Friesen[SUP] 3 4 [/SUP], Maria J P van Dongen[SUP] 3 6 8 [/SUP], Ian A Wilson[SUP] 9 10 [/SUP]
Affiliations
- PMID: 41413306
- DOI: 10.1038/s44298-025-00166-1
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.