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

Christopher J. Vavricka, Yue Liu, Hiromasa Kiyota, Nongluk Sriwilaijaroen, Jianxun Qi, Kosuke Tanaka, Yan Wu, Qing Li, Yan Li, Jinghua Yan, Yasuo Suzuki and George F. Gao ()
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Christopher J. Vavricka: Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science (BIOLS)
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
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
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)

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2487

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