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Structural characterization of influenza A polymerase PA subunit domains in complex with novel inhibitors
Radilová, Kateřina ; Kožíšek, Milan (advisor) ; Rumlová, Michaela (referee) ; Obšil, Tomáš (referee)
Influenza RNA-dependent RNA polymerase is a heterotrimeric complex and has an essential role in the life cycle of the virus. It is responsible for viral replication and transcription. One of its subunits, the polymerase acidic protein, interacts with the PB1 subunit via a crucial protein- protein interaction at its C-terminal domain. This 310 helix-mediated intersubunit interaction is required for the whole heterotrimer assembly. The N-terminal domain carries the endonuclease active site with two manganese ions. Both domains are considered promising drug targets. Current strategies to fight the influenza virus are limited to seasonal vaccines, and there are only a few anti-influenza drugs targeting mostly other viral proteins. Many used antivirals are susceptible to rapid resistance mutations development or cause severe side effects. This thesis provides structural insights into the two domains of the PA subunit. The first part is devoted to the characterization and optimization of a PB1-derived minimal peptide interacting with the C-terminal domain. Results from this part may be considered as a starting point for the rational design of first-in-class anti-influenza inhibitors of the PA-PB1 protein-protein interaction. In the other half, we have explored the inhibitory potency of flavonoids and...
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Epidemiological analysis of the incidence of influenza type A in the region Jindřichův Hradec with a comparison of the Jihočeský kraj (South region) for 2009 and 2010
NOVÁKOVÁ, Petra
The bulk of the thesis is focused on influenza A. The current theoretical knowledge in virological, epidemiological and clinical fields is summarized. Acute respiratory infections, including the influenza virus disorders, may be also caused by other agents. The most frequent agents which may be easily confused with influenza are also mentioned in the thesis in order to see the visible difference between these infections, which are often incorrectly referred to as influenza. The research part of the thesis deals with the epidemiological analysis of influenza incidence and its comparison in the district and regional levels. I have tried to evaluate the epidemiological situation within a two-year period. To compare the incidence of influenza A, I chose the Jindřichův Hradec region and compared the incidence in this region with that in the South Bohemian region. Both areas may be compared in terms of the diseases incidence, since all the data reported to the Regional Hygienic Station are standardized and calculated to the relative number of 100 000 inhabitants. I got the resources for the research at the Epidemiological department of the Regional Hygienic Station based in České Budějovice, where I used the EPIDAT program that is intended to ensure mandatory reporting, recording and analysis of infectious diseases in the Czech Republic, and looked up the necessary data for the 2009 and 2010 seasons. The data reported by general practitioners are divided into calendar weeks and age groups according to newly emerged diseases. However, individual types of influenza viruses are not mentioned, because not every acute respiratory disease is virologically verified in the laboratory or subsequent tests in the National Reference Laboratory are not carried out. Therefore, available data do not provide the exact incidence rates of influenza in a given period and place. Another important information resource was data on the tests frequency and the results of biological material laboratory tests which were conducted in the tracking period in the National Reference Laboratory for influenza. By analyzing available data it was possible to come to conclusion that in the tracking period influenza and influenza-like illness incidence rates did not reach the emergency epidemiological situation, even though in the region the epidemic threshold was crossed, it was only a short term condition.
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