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Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials
Dissertation (MSc (Biochemistry))--University of Pretoria, 2016.
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| Format: | Thesis |
| Language: | English |
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2026
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| _version_ | 1867613442430468096 |
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| access_status_str | Open Access |
| author2 | Birkholtz, Lyn-Marie |
| author_browse | Birkholtz, Lyn-Marie |
| author_facet | Birkholtz, Lyn-Marie |
| collection | Thesis |
| description | Dissertation (MSc (Biochemistry))--University of Pretoria, 2016. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/110102 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:36:12.984Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2026 |
| publishDateRange | 2026 |
| publishDateSort | 2026 |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/110102 Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials Birkholtz, Lyn-Marie jessica.connacher@gmail.com Niemand, Jandeli Connacher, Jessica Malaria Plasmodium Transcriptome Dissertation (MSc (Biochemistry))--University of Pretoria, 2016. The move toward global malaria eradication necessitates the discovery and development of effective antimalarials that target both the proliferative asexual parasite stages and the sexual asymptomatic stages that facilitate transmission to a new host. Furthermore, the immense replicative rate and thus mutational capacity of Plasmodium asexual parasites demands that new antimalarial chemotherapies have novel modes-of-action. In order for a new chemotherapy to progress through the development pipeline, its mode-of-action must be determined, thereby elucidating the downstream effects that occur as a result of target inhibition. Collectively, these effects are responsible for the global activities of the compound on a cell and can be determined using functional genomics. Functional genomics (transcriptomics, proteomics and metabolomics) rely on the availability of the genome sequence of the organism of interest to generate a dynamic topography of that organism. In the context of mode-of-action studies, functional genomics can be used to reveal the cell-wide response to chemotherapy. Transcriptomics profiles the entire mRNA population of a cell thereby providing a dynamic and genome-wide delineation of the cell of interest under an external perturbation. Transcriptomics (DNA microarray technology) was implemented in this project to determine the gene expression profiles and thus the mode-of-action of two clinical candidate antimalarial drugs, MMV390048 and UCT943, that are to be the first African-developed antimalarials. Substantial changes in the gene expression profiles of P. falciparum asexual parasites and early and late gametocytes were observed after treatment with ‘048 and ‘943. In asexual parasites, genes involved in transcription, translation and RNA splicing were differentially expressed. In early gametocytes, the two antimalarials perturbed the expression of genes involved in RNA processing and the metabolism of organic acids, macromolecules and proteins. Genes responsible for translation and the subsequent modification of protein products were differentially expressed in ‘048- and ‘943-treated late gametocytes. The disrupted expression of genes involved in these processes comprise the mode-of-action of ‘048 and ‘943 as PI4K inhibitors and give rise to the phenotypically observed potent cytocidal activity of these compounds against all the life cycle stages of malaria parasites in humans. v In addition, this study also describes the first gene expression fingerprint of drug-treated Plasmodium gametocytes. As such, the data generated serve as a blue print for future mode-ofaction deconvolution studies and the first evidence that RNA profiling may be employed toward this end. Indeed, the data indicate that gametocytes mount a transcriptional response within 24 hours of external perturbation, similar to asexual parasites. Therefore, although gametocytes are somewhat functionally and metabolically quiescent, their susceptibility to gametocytocidal chemotherapeutics is visible on a global transcriptomic scale. Taken together, the results generated in this study provide the first description of the mode-ofaction of the two clinical antimalarial candidates as well as serves as a foundational study to guide future drug development and mode-of-action deconvolution. Consequently, the data provide practical guidance for clinical implementation of ‘048 and ‘943, subsequent resistance monitoring and future drug discovery and development programs. Biochemistry MSc (Biochemistry) 2026-05-15T17:26:18Z 2026-05-15T17:26:18Z 17/02/03 2016 Dissertation http://hdl.handle.net/2263/110102 en |
| spellingShingle | Malaria Plasmodium Transcriptome Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials |
| title | Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials |
| title_full | Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials |
| title_fullStr | Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials |
| title_full_unstemmed | Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials |
| title_short | Deconvoluting drug mode-of-action : transcriptomic evaluation of novel clinical lead antimalarials |
| title_sort | deconvoluting drug mode of action transcriptomic evaluation of novel clinical lead antimalarials |
| topic | Malaria Plasmodium Transcriptome |
| url | http://hdl.handle.net/2263/110102 |