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A small molecule compound targeting hemagglutinin inhibits influenza A virus and exhibits broad-spectrum antiviral activity

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics.

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Fig. 1: Chemical structure of J1.
Fig. 2: Cytotoxicity and acute oral toxicity of compound J1.
Fig. 3: Broad-spectrum antiviral effects of J1.
Fig. 4: Inhibitory activity of J1 against A/WSN/1933 (H1N1) infection in vitro.
Fig. 5: J1 acts in the early stages of IAV infection and binds to HA.
Fig. 6: J1 inhibits IAV infection by blocking viral membrane fusion.
Fig. 7: Effect of J1 on H1N1 virus-induced ALI in mice.
Fig. 8: Survival protection of J1 on IAV-infected mice.

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Acknowledgements

We thank Shi-bo Jiang at Fudan University for the kindly gift of HA2 antibodies and guidance. This research was funded by the National Natural Science Foundation of China (Grant numbers 82073897, 82373915) and the Science and Technology Innovation Project of Guangdong Medical Products Administration (Grant numbers S2021ZDZ042). We thank BioRender for providing us with the drawing material.

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Authors and Affiliations

  1. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Yin-yan Li, Zhi-xuan Chen, Jin-long Liang, Lin-rui Jiang, Si-zu Yang, Feng Jiang, Shu-wen Liu & Jie Yang

  2. Key Laboratory for Candidate Drug Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Huhhot, 010110, China

    Guo-dong Liang

  3. Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province/Institute of Virology, School of Basic Medicine, Guizhou Medical University, Guiyang, 561113, China

    Ke Zhang

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Contributions

All authors contributed to the study conception and design. YYL and JY designed the research study. YYL and GDL conceived and carried out experiments. ZXC, KZ, and LRJ carried out animal experiments. JLL and LRJ coordinated the lung tissue collection of mice. YYL and SZY analyzed data. YYL, JY, FJ and SWL wrote and/or reviewed the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jie Yang.

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Li, Yy., Liang, Gd., Chen, Zx. et al. A small molecule compound targeting hemagglutinin inhibits influenza A virus and exhibits broad-spectrum antiviral activity. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01331-7

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