Computer-­‐aided design,synthesis and evaluation of novel anti-­‐chikungunya and anti-­‐enterovirus compounds

Zonsics, Birgit 2019. Computer-­‐aided design,synthesis and evaluation of novel anti-­‐chikungunya and anti-­‐enterovirus compounds. PhD Thesis, Cardiff University. Item availability restricted.

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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.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	19 December 2019
Last Modified:	31 Jul 2020 01:39
URI:	https://orca.cardiff.ac.uk/id/eprint/127629

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