Molecular studies of the Tacaribe virus nucleoprotein (NP): identification and characterisation of virus-host interactions as novel anti-arenavirus drug targets
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Arenaviruses cause an estimated 300,000 – 500,000 infections annually. Currently there is no arenavirus-specific antiviral drug available to treat these infections. This study sought to use the non-pathogenic New World arenavirus Tacaribe virus (TCRV) as a model for the pathogenic Junin virus (JUNV) and Machupo virus (MACV) that cause haemorrhagic fevers in South America. TCRV was used to explore three different approaches in the search for an antiviral drug against arenavirus infection targeted specifically against the viral nucleoprotein (NP). Of the four expressed arenaviral proteins, NP is the most abundant and is thought to be of multifunctional nature involved in viral replication, suppression of the innate immune system and viral egress. The approaches to find targets for broad-spectrum anti-arenaviral drugs were high throughput screens (HTS) with purified NP using thermal shift assays, exploring the virus interactions with the innate immune system and identifying virus-host protein-protein interactions. HTS resulted in the identification of two small-molecule compounds, [5-(2-Furyl)thien-2-yl]methanol and cyclosporine A (CsA), showing broad-spectrum activity against arenaviruses. Interferon-stimulated genes (ISGs), such as IFIT3, were identified to reduce viral titres and potential 202 protein-interactions between NP and host cell proteins were identified, of which the interaction with apoptosis-inducing factor 1 (AIF1) was described further. To characterise the importance of these interactions as potential drug targets further, a TCRV reverse genetics system was constructed.
Thesis, PhD Doctor of Philosophy
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