Dengue virus (DENV) is a health burden responsible of 50-100 million new cases and 22,000 deaths per year and its four serotypes are worryingly spreading out of the endemic regions. Current therapy is symptomatic, making antiviral research on DENV an unmet need. Vaccine development is more challenging than expected, so the development of anti-DENV drugs is particularly important for infection management. DENV is a positive sense single stranded RNA virus that replicates within cells exploiting both host and viral enzymes to replicate. Based on the hypothesis that DENV infection can be stopped with the inhibition of one or more of the enzymes that are fundamental for its replication, the aims of the studies reported in this PhD thesis were to: identify novel targets to combat DENV infection, generate new basic knowledge and discover potential novel chemical leads exploiting those targets. Novel approaches combining molecular modelling techniques, classical Medicinal Chemistry approaches, chemical synthesis and in& vitro assays were applied to four essential viral-encoded proteins: the capsid (C), the NS3 NTPase/helicase (NS3hel), the NS5 methyltransferase (NS5 MTase) and the NS5 RNA-dependent RNA polymerase (NS5 RdRp). Novel understanding of the 3'-5' translocation mechanism of NS3hel along the RNA has been hypothesised, increasing awareness about DENV-encoded proteins. Important knowledge on the mode of action of promising antiviral compounds has been acquired, for example that ST-148 stabilises C protein-protein interactions and that published N-sulphonylanthranilic acid RdRp inhibitors bind to a unique allosteric site. Novel promising DENV inhibitor scaffolds have also been developed and the chemical synthesis of one of them has been described, showing that the adopted drug discovery approaches are suitable starting points for the development of anti-DENV medicines. The results obtained represent a significant contribution to DENV research in increasing basic knowledge and in identifying good chemical leads for future work.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:642482 |
| Date | January 2014 |
| Creators | Trist, Iuni Margaret Laura |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/71338/ |
Page generated in 0.0017 seconds