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TitleMechanistic insights into the small-molecule inhibition of influenza A virus entry.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 33, Page e2503899122, Year 2025
Publish dateAug 19, 2025
AuthorsYan Xu / Varada Anirudhan / Irina N Gaisina / Haijuan Du / Saad Alqarni / Terry W Moore / Michael Caffrey / Balaji Manicassamy / Tongqing Zhou / Lijun Rong / Kai Xu /
PubMed AbstractInfluenza 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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:40802690 / PubMed Central
MethodsEM (single particle)
Resolution2.76 - 2.77 Å
Structure data

70657

9onz

EMDB-70657, PDB-9onz:
Influenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Complex with the Potent Small-Molecule Entry Inhibitor SA-67
Method: EM (single particle) / Resolution: 2.77 Å

70658

9oo1

EMDB-70658, PDB-9oo1:
Influenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Complex with a Potent Small-Molecule Entry Inhibitor ING-16-36
Method: EM (single particle) / Resolution: 2.76 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

PDB-1cc2:
CHOLESTEROL OXIDASE FROM STREPTOMYCES HIS447GLN MUTANT

PDB-1cc3:
PURPLE CUA CENTER

Source
  • influenza a virus
KeywordsVIRAL PROTEIN/INHIBITOR / Influenza A Virus / Hemagglutinin / Complex / Small-Molecule Inhibitor / Entry / SA-67 / VIRAL PROTEIN-INHIBITOR complex / ING-16-36

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