Design, Synthesis and Anti-Influenza Virus Activity of 4-Tert-Butyl-N-(3-Oxo-1-Thia-4-Azaspiro[4.5]Dec-4-yl)Benzamide Derivatives That Target Hemagglutinin-Mediated FusionÇınar, Alikadıoğlu, Soylu-Eter
et alDrug Dev Res (2025) 86 (2), e70080
Abstract: Hemagglutinin (HA) is a viral glycoprotein that mediates influenza virus entry into the host cell and is considered a relevant viral target. We here report the identification of a class of 4-tert-butylphenyl-substituted spirothiazolidinones as HA-mediated fusion inhibitors with specific activity against influenza A/H3N2 virus. The novel spirocyclic compounds were achieved by using one-pot cyclocondensation method and the chemical structures were characterized by IR, 1H NMR, 13C NMR, and elemental analysis. Compound 2c, bearing methyl substitutions at positions 2- and 8- of the spiro ring displayed an EC50 value against influenza A/H3N2 virus of 1.3 μM and an antiviral selectivity index of 30. The fusion-inhibiting effect of compound 2c was revealed in the polykaryon assay which is based on cell-cell fusion when influenza virus H3 HA-transfected cells are exposed to low pH. Computer-aided docking was performed to predict the possible binding pocket in the H3 HA trimer. Resistance data and in silico studies indicated that compound 2c has an overlapping binding pocket in the stem region of H3 HA with the known fusion inhibitors TBHQ and arbidol.© 2025 The Author(s). Drug Development Research published by Wiley Periodicals LLC.
Modulation of lipid nanoparticle-formulated plasmid DNA drives innate immune activation promoting adaptive immunityTursi, Tiwari, Bedanova
et alCell Rep Med (2025)
Abstract: Nucleic acid vaccines have grown in importance over the past several years, with the development of new approaches remaining a focus. We describe a lipid nanoparticle-formulated DNA (DNA-LNP) formulation which induces robust innate and adaptive immunity with similar serological potency to mRNA-LNPs and adjuvanted protein. Using an influenza hemagglutinin (HA)-encoding construct, we show that priming with our HA DNA-LNP demonstrated stimulator of interferon genes (STING)-dependent upregulation and activation of migratory dendritic cell (DC) subpopulations. HA DNA-LNP induced superior antigen-specific CD8+ T cell responses relative to mRNA-LNPs or adjuvanted protein, with memory responses persisting beyond one year. In rabbits immunized with HA DNA-LNP, we observed immune responses comparable or superior to mRNA-LNPs at the same dose. In an additional model, a SARS-CoV-2 spike-encoding DNA-LNP elicited protective efficacy comparable to spike mRNA-LNPs. Our study identifies a platform-specific priming mechanism for DNA-LNPs divergent from mRNA-LNPs or adjuvanted protein, suggesting avenues for this approach in prophylactic and therapeutic vaccine development.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Electro-active evanescent-wave cavity ring-down spectroscopy immunosensor for influenza virus detectionAlnaanah, Qatamin, Mendes
et alBiomed Opt Express (2025) 16 (3), 982-994
Abstract: The early and accurate detection of viral pathogens is critical for effective disease management and public health safety. This study introduces an immunosensor that integrates an electro-active evanescent-wave cavity ring-down spectroscopy (EW-CRDS) platform with a sandwich-type bioassay for label-free detection of the influenza A (H5N1) hemagglutinin (HA) protein, achieving a detection limit of 15 ng/mL. The sensor is constructed by functionalizing the EW-CRDS platform within a micro-electrochemical flow cell with a monoclonal antibody specific to the target antigen. Upon antigen binding, a secondary polyclonal antibody conjugated with a redox-active methylene blue dye is captured. This dye undergoes reversible optical signal changes during redox transitions, which are electrochemically modulated and detected with high sensitivity. Unlike conventional approaches, this sensor employs electrochemical modulation to amplify surface-specific optical signals while reducing processing time and minimizing background noise. The results demonstrate the potential of this technology for real-time monitoring and rapid, reliable diagnosis of infectious diseases, offering excellent sensitivity and ease of operation in detecting influenza viruses. This work highlights the promise of the electro-active EW-CRDS platform for antigen detection in clinical settings.© 2025 Optica Publishing Group.
Pathogenicity and transmissibility of bovine-derived HPAI H5N1 B3.13 virus in pigsKwon, Trujillo, Carossino
et albioRxiv (2025)
Abstract: Since the first emergence of highly pathogenic avian influenza (HPAI) H5N1 viruses in dairy cattle, the virus has continued to spread, reaching 17 states and at least 970 dairy herds in the United States. Subsequently, spillovers of the virus from dairy cattle to humans have been reported. Pigs are an important reservoir in influenza ecology because they serve as a mixing vessel in which novel reassortant viruses with pandemic potential can be generated. Here, we show that oro-respiratory infection of pigs resulted in productive replication of a bovine-derived HPAI H5N1 B3.13 virus. Infectious virus was mainly identified in the lower respiratory tract of principal infected pigs, and sero-conversion was observed in most of the principal pigs at later time points. In one animal, we detected the emergence of a mutation in hemagglutinin (HA) previously associated with increased affinity for "mammalian-type" α2,6-linked sialic acid receptors, but this mutation did not reach consensus levels. Sentinel contact pigs remained sero-negative throughout the study, indicating lack of transmission. The results support that pigs are susceptible to a bovine-derived HPAI H5N1 B3.13 virus, but this virus did not replicate as robustly in pigs as mink-derived HPAI H5N1 and swine-adapted influenza viruses.
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