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Identification of anti-poxviral agents by high-throughput image-based screening

Samolej, Jerzy; (2019) Identification of anti-poxviral agents by high-throughput image-based screening. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Poxviruses are a family of large, double-stranded DNA viruses that infect a wide range of organisms, from insects to humans. They possess a complex structure and an intricate replication cycle that takes place entirely in the cytoplasm. Additionally, their genome is remarkably large for viruses, encoding over 200 proteins. Historically, one representative of the orthopox genera – variola virus, the causative agent of smallpox – has claimed hundreds of millions of human lives. Despite its eradication, smallpox, and some zoonotic poxviruses, are still considered as potential threats, and new means of combating them are in demand. To this end research has continued on vaccinia virus (VACV), the prototypic orthopox virus which was used as the smallpox vaccine. In this project a library of 1,280 FDA approved molecules was screened for cell-based VACV inhibitors using a high-throughput image-based screen, following the principles of drug repurposing. After confirmation of initial hits using secondary screens, 9 Early inhibitors, 3 Late inhibitors, and 7 Spread inhibitors were identified. Additionally, 14 cardiac glycosides were identified as Early inhibitors. Using focused assays, the specific phases of the virus replication cycle at which inhibition occurs were also identified. This project led to the discovery of new compounds that block VACV infection at different stages in cell culture. Additionally, the initial hits were tested on African swine fever virus and 5 potential inhibitors were identified. Collectively, these results have furthered our insights into host – pathogen interaction, while providing potential hits for testing in animal models and against other viruses.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Identification of anti-poxviral agents by high-throughput image-based screening
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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: vaccinia, virus, drug screen
UCL classification: UCL
UCL > Provost and Vice Provost Offices
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
URI: https://discovery.ucl.ac.uk/id/eprint/10084542
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