9ONZ

Influenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Complex with the Potent Small-Molecule Entry Inhibitor SA-67

This is a non-PDB format compatible entry.

Summary for 9ONZ

• Entry DOI: 10.2210/pdb9onz/pdb
• EMDB information: 70657
• Descriptor: Hemagglutinin HA1, Hemagglutinin HA2, oligosaccharide, ... (5 entities in total)
• Functional Keywords: influenza a virus, hemagglutinin, complex, small-molecule inhibitor, entry, sa-67, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Influenza A virus; More
• Total number of polymer chains: 6
• Total formula weight: 173812.93

Authors

Xu, Y.,Xu, K. (deposition date: 2025-05-15, release date: 2025-07-16, Last modification date: 2025-08-27)

Primary citation

Xu, Y.,Anirudhan, V.,Gaisina, I.N.,Du, H.,Alqarni, S.,Moore, T.W.,Caffrey, M.,Manicassamy, B.,Zhou, T.,Rong, L.,Xu, K.
Mechanistic insights into the small-molecule inhibition of influenza A virus entry.
Proc.Natl.Acad.Sci.USA, 122:e2503899122-e2503899122, 2025

PubMed Abstract: Influenza A virus (IAV) is a zoonotic pathogen responsible for seasonal and pandemic flu. The extensive genetic and antigenic diversity within and between IAV phylogenetic groups presents major challenges for developing universal vaccines and broad-spectrum antiviral therapies. Current interventions provide limited protection due to the virus's high mutation rate and capacity for immune evasion. Recent advancements in viral hemagglutinin (HA)-targeting small-molecule entry inhibitors offer a promising avenue to overcome these limitations. Here, we present structural and functional analyses of two group 2 HA-specific small-molecule inhibitors recently identified by our team. Cryogenic electron microscopy (cryo-EM) structures revealed that these inhibitors bind a conserved pocket within the HA stalk, likely interfering with the conformational rearrangements necessary for membrane fusion and viral entry. Structure-guided mutagenesis confirmed the critical roles of key interacting residues and uncovered distinct resistance profiles between the two compounds, as well as in comparison to Arbidol, a previously reported HA inhibitor. Notably, our structural analysis highlights intrinsic barriers to achieving cross-group inhibition with current small-molecule designs. To address this, we propose an alternative strategy for broadening antiviral coverage. Together, these findings provide mechanistic insights into IAV entry inhibition and a foundation for the rational design of next-generation anti-influenza therapeutics.

PubMed: 40802690
DOI: 10.1073/pnas.2503899122

Experimental method

ELECTRON MICROSCOPY (2.77 Å)