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Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents / BEN FLUDE

Swansea University Author: BEN FLUDE

  • E-Thesis under embargo until: 1st July 2026

DOI (Published version): 10.23889/SUThesis.67730

Abstract

An important new tool in combating viral disease is the creation and use of broad-spectrumantivirals. In the post-COVID pandemic world, the need for such drugs is more evident thanever. In this work, potential broad-spectrum antiviral agents have been developed for twofamilies of viruses, Clade B of...

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Published: Swansea University, Wales, UK 2024
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Bassetto, M., and Carta, M.
URI: https://cronfa.swan.ac.uk/Record/cronfa67730
first_indexed 2024-09-19T10:51:27Z
last_indexed 2024-11-25T14:20:43Z
id cronfa67730
recordtype RisThesis
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spelling 2024-09-19T12:36:38.2388626 v2 67730 2024-09-19 Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents 69870c33c22a615fbb7a5bcecde912af BEN FLUDE BEN FLUDE true false 2024-09-19 An important new tool in combating viral disease is the creation and use of broad-spectrumantivirals. In the post-COVID pandemic world, the need for such drugs is more evident thanever. In this work, potential broad-spectrum antiviral agents have been developed for twofamilies of viruses, Clade B of the New World arenaviruses, and the highly pathogenic human coronaviruses. This has been achieved by identifying conserved protein-protein interactions within the virus families using in silico techniques, for which inhibitors have been designed and synthesised, and the inhibitory activities quantified by in vitro testing. In the case of New World arenaviruses, previous work completed in group had identified two hit antiviral molecules, for which different series of diverse analogues have been synthesised and evaluated for inhibition of the interaction between the viral glycoprotein 1 and host human transferrin receptor 1, the protein-protein interaction required for cell entry for all members of Clade B. For the highly pathogenic human coronaviruses, an in-silico interaction model was created for the conserved interaction between the viral nucleocapsid protein and host mannose-binding lectin associated serine protease 2, which was used as the basis for a drug repurposing study and a virtual screening of a drug-like small molecule library, from which two hit molecules have been identified. In parallel to this structure-based approach, a ligand-based approach was also taken using a conserved amino acid sequence found in the nucleocapsid proteins that is responsible for the protein-protein interaction, from whichnovel peptidomimetic molecules were designed, and a synthetic route for these compoundshas been optimised. Multiple series of anti-arenavirus molecules have been synthesised,identifying two species that have progressed into in vivo studies, showing improved activityover the previously identified hit molecule. A protein-protein interaction model of MASP-2 incomplex with the N protein of SARS-CoV-2 has been developed, used as the basis for a virtual screening study identifying two hit molecules, with a series of peptidomimetic molecules being designed and a suitable synthetic route created based on the interacting sequence of the SARS-CoV-2 N protein. E-Thesis Swansea University, Wales, UK Medicinal Chemistry, Organic Chemistry, Antivirals 18 4 2024 2024-04-18 10.23889/SUThesis.67730 A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. COLLEGE NANME COLLEGE CODE Swansea University Bassetto, M., and Carta, M. Doctoral Ph.D EPSRC Doctoral Training Grant EPSRC Doctoral Training Grant 2024-09-19T12:36:38.2388626 2024-09-19T11:27:45.2324137 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry BEN FLUDE 1 Under embargo Under embargo 2024-09-19T11:50:01.0890737 Output 17951468 application/pdf E-Thesis true 2026-07-01T00:00:00.0000000 Copyright: The Author, Ben Flude, 2024 true eng
title Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
spellingShingle Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
BEN FLUDE
title_short Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
title_full Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
title_fullStr Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
title_full_unstemmed Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
title_sort Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents
author_id_str_mv 69870c33c22a615fbb7a5bcecde912af
author_id_fullname_str_mv 69870c33c22a615fbb7a5bcecde912af_***_BEN FLUDE
author BEN FLUDE
author2 BEN FLUDE
format E-Thesis
publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUThesis.67730
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 0
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description An important new tool in combating viral disease is the creation and use of broad-spectrumantivirals. In the post-COVID pandemic world, the need for such drugs is more evident thanever. In this work, potential broad-spectrum antiviral agents have been developed for twofamilies of viruses, Clade B of the New World arenaviruses, and the highly pathogenic human coronaviruses. This has been achieved by identifying conserved protein-protein interactions within the virus families using in silico techniques, for which inhibitors have been designed and synthesised, and the inhibitory activities quantified by in vitro testing. In the case of New World arenaviruses, previous work completed in group had identified two hit antiviral molecules, for which different series of diverse analogues have been synthesised and evaluated for inhibition of the interaction between the viral glycoprotein 1 and host human transferrin receptor 1, the protein-protein interaction required for cell entry for all members of Clade B. For the highly pathogenic human coronaviruses, an in-silico interaction model was created for the conserved interaction between the viral nucleocapsid protein and host mannose-binding lectin associated serine protease 2, which was used as the basis for a drug repurposing study and a virtual screening of a drug-like small molecule library, from which two hit molecules have been identified. In parallel to this structure-based approach, a ligand-based approach was also taken using a conserved amino acid sequence found in the nucleocapsid proteins that is responsible for the protein-protein interaction, from whichnovel peptidomimetic molecules were designed, and a synthetic route for these compoundshas been optimised. Multiple series of anti-arenavirus molecules have been synthesised,identifying two species that have progressed into in vivo studies, showing improved activityover the previously identified hit molecule. A protein-protein interaction model of MASP-2 incomplex with the N protein of SARS-CoV-2 has been developed, used as the basis for a virtual screening study identifying two hit molecules, with a series of peptidomimetic molecules being designed and a suitable synthetic route created based on the interacting sequence of the SARS-CoV-2 N protein.
published_date 2024-04-18T05:23:34Z
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score 11.089386

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