9PHD

Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with fusion inhibitor cyclic peptide CP141076 (CP8)

This is a non-PDB format compatible entry.

Summary for 9PHD

• Entry DOI: 10.2210/pdb9phd/pdb
• Descriptor: Hemagglutinin, Hemagglutinin HA2 chain, cyclic peptide CP141076, ... (9 entities in total)
• Functional Keywords: influenza virus, hemagglutinin, fusion inhibitors, cyclic peptide, viral protein
• Biological source: Influenza A virus (A/Puerto Rico/8/1934(H1N1)); More
• Total number of polymer chains: 3
• Total formula weight: 60373.36

Authors

Kadam, R.U.,Wilson, I.A. (deposition date: 2025-07-09, release date: 2025-12-24, Last modification date: 2025-12-31)

Primary citation

Kadam, R.U.,Juraszek, J.,Brandenburg, B.,Garg, D.,Zhu, X.,Jongeneelen, M.,Schepens, W.B.G.,Stoops, B.,Vermond, J.,Goutier, W.,Tang, C.,Blokland, S.,Vogels, R.,Friesen, R.H.E.,van Dongen, M.J.P.,Wilson, I.A.
V H H antibody loop guides design of a synthetic macrocyclic peptide that potently blocks influenza virus membrane fusion.
Npj Viruses, 3:83-83, 2025

PubMed Abstract: 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 (VH) llama antibody as a starting point for peptide design. VH 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 VH antibody. One such macrocycle peptide candidate is promising for further development of broad protection against influenza A group 1 viruses.

PubMed: 41413306
DOI: 10.1038/s44298-025-00166-1

Experimental method

X-RAY DIFFRACTION (1.59 Å)