Abstract
This chapter presents a review of the development of influenza virus sialidase inhibitors based on a carbohydrate scaffold, predominantly that of the natural ‘ligand’ of the enzyme, N-acetylneuraminic acid (Neu5Ac). These inhibitors include hydrolytically stable substrate-like compounds, product mimics, and transition-state-like compounds. The major focus of the chapter, reflecting the most intensively researched area of inhibitor development, is on the use of the dihydropyran scaffold of the 2,3-unsaturated-Neu5Ac derivative, Neu5Ac2en, a putative transition state mimic. Structure-based drug design targeting conserved residues of the sialidase active site using this template leading to the development of the potent and selective inhibitor, and anti-influenza drug, zanamivir (Relenza™), as well as subsequent developments towards next generation inhibitors, are discussed.
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Abbreviations
- NA:
-
Neuraminidase (sialidase)
- Neu5Ac:
-
N-acetylneuraminic acid
- Neu5Ac2en:
-
2-deoxy-2,3-didehydro-N-acetylneuraminic acid
- MDCK:
-
Madin-Darby canine kidney (cell line)
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The financial support of the Australian Research Council (ARC) through the award of an Australian Federation Fellowship (MvI), the National Health and Medical Research Council (NHMRC), and the Honda Foundation (Australia) is gratefully acknowledged.
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Thomson, R., von Itzstein, M. (2012). The Development of Carbohydrate-Based Influenza Virus Sialidase Inhibitors. In: von Itzstein, M. (eds) Influenza Virus Sialidase - A Drug Discovery Target. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-7643-8927-7_5
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