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Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors

Author

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  • Christopher J. Vavricka

    (Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science (BIOLS)
    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Yue Liu

    (CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Hiromasa Kiyota

    (Graduate School of Agricultural Science, Tohoku University)

  • Nongluk Sriwilaijaroen

    (Faculty of Medicine, Thammasat University
    College of Life and Health Sciences, Chubu University)

  • Jianxun Qi

    (CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Kosuke Tanaka

    (Graduate School of Agricultural Science, Tohoku University)

  • Yan Wu

    (CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Qing Li

    (CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
    School of Life Sciences, University of Science and Technology of China)

  • Yan Li

    (CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Jinghua Yan

    (CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Yasuo Suzuki

    (College of Life and Health Sciences, Chubu University)

  • George F. Gao

    (Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science (BIOLS)
    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
    School of Life Sciences, University of Science and Technology of China
    Chinese Center for Disease Control and Prevention (China CDC))

Abstract

Development of novel influenza neuraminidase inhibitors is critical for preparedness against influenza outbreaks. Knowledge of the neuraminidase enzymatic mechanism and transition-state analogue, 2-deoxy-2,3-didehydro-N-acetylneuraminic acid, contributed to the development of the first generation anti-neuraminidase drugs, zanamivir and oseltamivir. However, lack of evidence regarding influenza neuraminidase key catalytic residues has limited strategies for novel neuraminidase inhibitor design. Here, we confirm that influenza neuraminidase conserved Tyr406 is the key catalytic residue that may function as a nucleophile; thus, mechanism-based covalent inhibition of influenza neuraminidase was conceived. Crystallographic studies reveal that 2α,3ax-difluoro-N-acetylneuraminic acid forms a covalent bond with influenza neuraminidase Tyr406 and the compound was found to possess potent anti-influenza activity against both influenza A and B viruses. Our results address many unanswered questions about the influenza neuraminidase catalytic mechanism and demonstrate that covalent inhibition of influenza neuraminidase is a promising and novel strategy for the development of next-generation influenza drugs.

Suggested Citation

  • Christopher J. Vavricka & Yue Liu & Hiromasa Kiyota & Nongluk Sriwilaijaroen & Jianxun Qi & Kosuke Tanaka & Yan Wu & Qing Li & Yan Li & Jinghua Yan & Yasuo Suzuki & George F. Gao, 2013. "Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2487
    DOI: 10.1038/ncomms2487
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