Target indicators and mechanistic function of epidrugs with activity against multiple stages of Plasmodium falciparum parasites

dc.contributor.advisorBirkholtz, Lyn-Marie
dc.contributor.coadvisorReader, Janette
dc.contributor.emaildaniel.opperman@gmail.comen_ZA
dc.contributor.postgraduateOpperman, Daniel Francis Luke
dc.date.accessioned2022-02-15T12:56:47Z
dc.date.available2022-02-15T12:56:47Z
dc.date.created2022
dc.date.issued2021
dc.descriptionDissertation (MSc (Biochemistry))--University of Pretoria, 2021.en_ZA
dc.description.abstractResistance to the most widely used drugs in the treatment of malaria, those in artemisinin-based combination therapies, has emerged, most recently in Africa. Development of new drugs that exploit unique structures with new modes of action (MoA) is therefore critical. There is also a need for the development of compounds with transmission-blocking activity, in addition to the clearance of symptom-causing stages associated with drugs currently part of the chemotherapeutic toolbox. A promising avenue of research in this regard is into epigenetic drugs (“epidrugs”), which target epigenetic mechanisms of transcriptional control, resulting in parasite death through perturbation of gene expression. A selection of compounds with demonstrated epigenetic perturbation in human cancer cell lines have shown favourable inhibitory profiles against Plasmodium falciparum parasites. For a number of these compounds, the specific mode of action remained to be elucidated and characterised. This dissertation has contributed to our understanding of these compounds’ modes of action, demonstrating perturbation of histone post-translational modifications, and revealing possible binding modes to putative targets through in silico predictions. Findings confirmed histone deacetylase inhibition for both Scriptaid and Sirtinol, with histone deacetylase 1 (PfHDAC1) and sirtuin 2A (PfSir2A), respectively, indicated as the targets of these compounds through in silico docking studies. ML324 was found to exhibit histone demethylase activity in P. falciparum late-stage gametocytes, with PfJmj3 indicated as the target of this compound. Finally, the potential of these compounds as transmission-blocking drugs has been revealed through exflagellation inhibition assays and confirmed with standard membrane-feeding assays. These results underscore the potential of epigenetic transcriptional control as a targetable biology, and of epidrugs to contribute towards addressing the development of drug resistance by P. falciparum. The findings demonstrated in this dissertation may lay the groundwork for future drug development efforts for which the epigenetic drugs discussed here may serve as chemical scaffolds.en_ZA
dc.description.availabilityUnrestricteden_ZA
dc.description.degreeMSc (Biochemistry)en_ZA
dc.description.departmentBiochemistryen_ZA
dc.description.sponsorshipNational Research Foundation (NRF)en_ZA
dc.identifier.citation*en_ZA
dc.identifier.otherA2022en_ZA
dc.identifier.urihttp://hdl.handle.net/2263/83937
dc.language.isoenen_ZA
dc.publisherUniversity of Pretoria
dc.rights© 2022 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria.
dc.subjectBiochemistryen_ZA
dc.subjectPlasmodium falciparum parasites
dc.subjectEpidrugs
dc.subjectUCTD
dc.titleTarget indicators and mechanistic function of epidrugs with activity against multiple stages of Plasmodium falciparum parasitesen_ZA
dc.typeDissertationen_ZA

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