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Preparation of Influenza Neuraminidase and Polymerase Inhibitors
Zima, Václav ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza is an infectious disease caused by the influenza virus. This virus causes a severe viral infection that spreads easily from person to person in yearly pandemics. Vaccination is the most effective way to prevent the infection, however, due to the high rate in mutations of the virus, the vaccine needs to be often reformulated. Another option to combat influenza is based on administration of antiviral drugs. Clinical studies of isolated influenza strains ("avian flu" H5N1, 2004; "swine flu" H1N1, 2009) revealed resistance towards known influenza neuraminidase inhibitors (zanamivir, oseltamivir). The resistance is caused by structural changes close to the enzymatic site. This calls for the development of new neuraminidase inhibitors as well for development of inhibitors targeting different influenza enzymes. This Thesis is focused on design and synthesis of new inhibitors of influenza neuraminidase and RNA-dependent RNA polymerase, namely PA subunit and the assembly of PA-PB1 heterodimer enzymes (Scheme 1). Influenza neuraminidase inhibitors were prepared by C-5 derivatization of oseltamivir followed by subsequent extension of its structure with binders of 150-cavity. Binding potencies of new oseltamivir derivatives against two influenza strains were determined. The next part contributed to...
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