Mechanistic insights into the small-molecule inhibition of influenza A virus entry

• 成果类型: Article
• 署名作者: Xu, Yan; Anirudhan, Varada; Gaisina, Irina N.; Du, Haijuan; Alqarni, Saad; Moore, Terry W.; Caffrey, Michael; Manicassamy, Balaji; Zhou, Tongqing; Rong, Lijun; Xu, Kai
• 署名单位: University System of Ohio; Ohio State University; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); University Ha'il; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Iowa; University System of Ohio; Ohio State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11934
• DOI: 10.1073/pnas.2503899122
• 发表日期: 2025-08-19
• 关键词: conformational-change; antigenic drift; hemagglutinin; optimization; vaccination; validation; vaccines; arbidol; MODEL

摘要

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.