Journal article
Mechanistic insights into the small-molecule inhibition of influenza A virus entry
Proceedings of the National Academy of Sciences - PNAS, Vol.122(33), e2503899122
08/19/2025
DOI: 10.1073/pnas.2503899122
PMCID: PMC12377760
PMID: 40802690
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.
Details
- Title: Subtitle
- Mechanistic insights into the small-molecule inhibition of influenza A virus entry
- Creators
- Yan Xu - The Ohio State UniversityVarada Anirudhan - University of Illinois Urbana-ChampaignIrina N Gaisina - University of Illinois Urbana-ChampaignHaijuan Du - National Institute of Allergy and Infectious DiseasesSaad Alqarni - University of Ha'ilTerry W Moore - University of Illinois Urbana-ChampaignMichael Caffrey - University of Illinois Urbana-ChampaignBalaji Manicassamy - University of IowaTongqing Zhou - National Institute of Allergy and Infectious DiseasesLijun Rong - University of Illinois Urbana-ChampaignKai Xu - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.122(33), e2503899122
- DOI
- 10.1073/pnas.2503899122
- PMID
- 40802690
- PMCID
- PMC12377760
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Publisher
- NATL ACAD SCIENCES
- Grant note
- R41AI145727 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R42AI155039 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) UH2 AI171611 / NIAID NIH HHS Path to K award / OSU | Center for Clinical and Translational Science, Ohio State University (CCTS, OSU) U01 AI173348 / NIAID NIH HHS
- Language
- English
- Date published
- 08/19/2025
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984946701902771
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