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The Development of Carbohydrate-Based Probes of Influenza Virus Sialidase

By Mauro Pascolutti

Abstract

Influenza is a significant human disease, as evidenced by seasonal epidemics that exact a high toll in morbidity and mortality, and worldwide pandemics, for example the 2009 'swine-origin' influenza A pandemic. Two influenza virus-specific drugs, Relenza® and Tamiflu®, target the viral enzyme sialidase, and are effective against all wild type influenza virus strains. Resistance development to the more widely used drug, Tamiflu®, however, and new insights into the sialidase structure, have fuelled a drive to develop new sialidase inhibitors. The research described in this PhD thesis is focused on the development of novel carbohydrate-based inhibitors of influenza virus sialidase. This enzyme plays an important role in the process of infection by facilitating the release of new virus particles from the infected host cell. Inhibition of the viral sialidase leaves new virus particles clumped at the infected cell surface, thus reducing propagation of infection. Recent X-ray crystal structures of a sub-group of influenza A virus sialidases, which includes the important N1 sialidases, have revealed a previously unanticipated cavity adjacent to the enzyme active site, which is formed upon the opening of a flexible protein loop (the 150-loop). This offers the potential for the design of new sialidase inhibitors that target the open 150-loop conformation of the protein. Work published in the von Itzstein group has shown that suitable C-linked functionality introduced at the C3 position of the general sialidase inhibitor Neu5Ac2en, can extend into the 150-cavity and lock the flexible 150-loop in an open conformation. The research undertaken in this work, to further explore inhibition of influenza virus sialidase by targetting the 150-cavity, involved the synthesis of 3-O- and 3-N-substituted Neu5Ac2en derivatives.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Institute for GlycomicsScience, Environment, Engineering and TechnologyFull Tex

Topics: Influenza, Influenza A pandemic, Viral enzyme sialidase, Relenza®, Tamiflu®, Influenza virus sialidase
Publisher: Griffith University
Year: 2013
OAI identifier: oai:research-repository.griffith.edu.au:10072/366410
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