Dulson, Christopher;
(2025)
Targeting the Transcription System of
African Swine Fever Virus for
Antiviral Drug Discovery.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
African Swine Fever Virus (ASFV) infects domestic pigs inducing a lethal haemorrhagic fever in greater than 90% of instances. ASFV continues to spread globally with devasting effects on the swine farming industry and threatens global food security. Currently, no antiviral drugs have been approved for use against ASFV. A promising target for therapeutic intervention is the viral transcription system, which relies solely on a viral RNA polymerase (vRNAP) and transcription factors. In this research, viral proteins predicted to be involved in viral transcription were produced recombinantly and functionally characterised both in terms of catalysis and protein-protein interactions. The recombinant vRNAP was active at transcription and an assay with effective fluorescence-based output which could be performed at high throughput was developed. Additionally, compounds were screened for inhibitory effects, in turn leading to the discovery of seven inhibitors of the vRNAP transcription activity, the top five of which had half maximal inhibitory concentrations (IC50) of 25-52 μM. The top five compounds were also shown to be selective for inhibition of the viral RNAP over eukaryotic RNA polymerase II. The work presented offers the potential for the discovery and development of new antiviral drugs against the ASFV transcription system, which could prove effective in managing the disease and controlling the spread of outbreaks. The predicted transcription factors for the early stages of infection D1133L and Q706L, in agreement with sequence analysis, exhibited ATPase activity, which was DNA independent and dependent, respectively. Additionally, the activity of D1133L was only observed when in complex with G1340L. The discovery of ATPase activity in these transcription factors presents a new target for the development of antiviral drugs.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Targeting the Transcription System of African Swine Fever Virus for Antiviral Drug Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | African Swine Fever Virus, D1133L, G1340L, Q706L, RNA Polymerase, Transcription, ATPase, Transcription Inhibitor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213277 |
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