Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.794739
Title: Computer-aided design, synthesis and evaluation of novel anti-chikungunya and anti-enterovirus compounds
Author: Zonsics, Birgit
ISNI:       0000 0004 8500 806X
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2019
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Abstract:
RNA viruses present a large group of viruses that contains many important human pathogens. Chikungunya virus is an Alphavirus transmitted by tiger mosquitoes, causing a febrile disease that often leads to very disabling, sometimes chronic, joint and muscular pain that can last for several weeks up to months. The Picornaviridae family including enterovirus A71, coxsackievirus B3, poliovirus, enterovirus D68 and rhinoviruses cause various different clinical symptoms and diseases like hand-foot-and-mouth disease, poliomyelitis, or the common cold. For none of these viruses direct-acting antivirals are on the market yet, stressing the need to design novel compounds that could target these viruses and that may enter into (pre-)clinical development soon. The replication cycle of RNA viruses requires specific viral proteins that replicate the viral genome and fulfil other crucial functions within the host-cell but are not packed into new viral particles. These non-structural proteins present excellent targets to inhibit the viral replication and were therefore investigated using computer-aided techniques in order to find novel antiviral compounds. Pharmacophore screening and docking were used to select molecules from large chemical libraries that were then tested in cell-based antiviral assays for their activities. Then the compounds were synthesised and improved using classic medicinal- chemistry modifications. For chikungunya several different compounds with low micromolar activity could be identified. For the picornaviruses several inhibitors were reported, but the exact mode-of-action on their molecular target (2C protein) was unknown. Possible sites and interactions were explored using site identification tools, docking and molecular dynamics simulations. In collaboration with virologists and structural biologists this lead to the clarification of the mode-of-action of fluoxetine, which exhibits a stereoselective activity on 2C. In addition, a series of novel inhibitors with broad-spectrum activity against the described picornaviruses was developed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.794739  DOI: Not available
Keywords: Q Science (General)
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