Margit Mutso will defend her doctoral thesis titled “Different Approaches to Counteracting Hepatitis C Virus and Chikungunya Virus Infections” on 18 February 2016 at 14.15 at Nooruse street 1-121.
Supervisors: vanemteadur Eva Žusinaite (Tartu Ülikool), prof. Andres Merits (Tartu Ülikool)
Opponent: Prof. Mark Harris, PhD, School of Molecular and Cellular Biology, University of Leeds, UK
Viruses have been and will be an important part of every ecosystem. In the past, viral outbreaks have left painful marks on mankind. Using vaccines and antivirals has greatly reduced the number of infections and virus-caused pathology. Despite extensive research, some viruses and viral diseases are still lacking any good vaccine or treatment. Viral features like high mutation rate, complexity of viral lifecycle and genome diversity are only some of the obstacles needed to overcome for antivirals and vaccines to be safe and efficient.
Hepatitis C virus (HCV) is associated with different liver pathologies and it is estimated that approximately 3% of the world population is chronically infected with HCV. It is lacking efficient vaccine and the options for combating HCV infection, HCV-induced pathology, spread and persistence are limited to the use of antiviral drugs. One part of this dissertation is focused on the development of anti-HCV inhibitors using two different technological approaches. Firstly, a new FQSAR method based approach allowed rapid prediction of hit compounds targeting the NS3/4A protease of HCV. Seven compounds analysed in this project displayed some anti-HCV properties but only the effect caused by the non-cytotoxic compound 23332 can be considered to be direct. Secondly, a novel technology – incorporation of naturally occurring minimally modified nucleobases into ASOs – was evaluated using ASOs binding to the HCV non-structural region. This approach led to the development of ASO compounds with high anti-HCV activity. The technology based on the use of novel modified ONs is promising as well for the development antivirals for other viruses and diseases.
Chikungunya virus (CHIKV) re-emerged in the past decade and is currently spreading around the world, affecting millions of people. The second part of this study is focused on the analysis of a laboratory-developed attenuated CHIKV vaccine strain. CHIKVΔ5nsP3 and CHIKVΔ6K viruses were found to have a stably attenuated phenotype and the introduced molecular changes were maintained during serial passages. From all studied vaccine candidates the CHIKVΔ5nsP3 was the most potent. Further studies revealed that the region removed from CHIKVΔ5nsP3 vaccine candidate, is apparently involved in interactions with another domain of nsP3 as well as with the C-terminal region of nsP2. These findings provide a platform for further analysis of biological reasons for the attenuation of CHIKVΔ5nsP3 vaccine candidate.