Anti-Influenza Drugs: The Development of Sialidase Inhibitors
Viruses, particularly those that are harmful to humans, are the ‘silent terrorists’ of the twenty-first century. Well over four million humans die per annum as a result of viral infections alone. The scourge of influenza virus has plagued mankind througho
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Contents 1
Influenza: The Virus and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 The Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Influenza Virus Sialidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Structure and Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Sialidase as a Drug Discovery Target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 The Discovery of Zanamivir, the First Potent Designer Anti-Influenza Drug . . . . . 3.2 The Discovery of Oseltamivir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Further Developments of Influenza Virus Sialidase Inhibitors . . . . . . . . . . . . . . . . . 4 Clinical Application of Influenza Virus Sialidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . 5 Resistance Development to Sialidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Structural Basis of Resistance, and Cross-Resistance, to Sialidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Viruses, particularly those that are harmful to humans, are the ‘silent terrorists’ of the twenty-first century. Well over four million humans die per annum as a result of viral infections alone. The scourge of influenza virus has plagued mankind throughout the ages. The fact that new viral strains emerge on a regular basis, particularly out of Asia, establishes a continual socio-economic threat to mankind. The arrival of the highly pathogenic avian influenza H5N1 heightened the threat of a potential human pandemic to the point where many countries have put in place ‘preparedness plans’ to defend against such an outcome. The discovery of the TM first designer influenza virus sialidase inhibitor and anti-influenza drug Relenza , TM and subsequently Tamiflu , has now inspired a number of continuing efforts towards the discovery of next generation anti-influenza drugs. Such drugs may act M. von Itzstein () Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia [email protected] H.-G. Kr¨ausslich,
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