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Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites
Dissertation (MSc (Biochemistry))--University of Pretoria, 2024.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2025
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| _version_ | 1867613448351776768 |
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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 |
| dc_rights_str_mv | © 2023 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. |
| description | Dissertation (MSc (Biochemistry))--University of Pretoria, 2024. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/100338 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:36:18.633Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/100338 Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites Birkholtz, Lyn-Marie tyrickwelcome2@gmail.com Welcome, Tyrick UCTD Sustainable Development Goals (SDGs) Plasmodium falciparum Malaria Targeted protein degradation Proteolysis-targeting chimera (PROTAC) Epigenetics Dissertation (MSc (Biochemistry))--University of Pretoria, 2024. With the continuous emergence and spread of resistance to the only remaining effective antimalarial, artemisinin, novel drugs with novel modes-of-action (MoA) are needed. Current antimalarial efforts aim to identify small-molecule inhibitors that bind to the active site of essential target proteins, thereby killing the causative organism, Plasmodium falciparum. However, such active site-dependent inhibitors face the major challenge of resistance development. We therefore proposed the use of Proteolysis-targeting chimeras (PROTACs) that can induce the degradation of a target protein via the cells ubiquitin-proteasome system rather than inhibiting it. Ideally, for PROTACs to be effective in malaria research, they should bind to essential proteins, such as epigenetic modulators. Here we aimed to evaluate if PROTACs (MZ1 and VZ185) targeting epigenetic mechanisms have activity against P. falciparum parasites and if they are active due to a unique MoA. Both PROTACs were found to be active against the asexual developmental stages of P. falciparum parasites, while VZ185 was found to also be active against the gametocyte stages, implicating multistage activity. The PROTACs additionally showed nanomolar activity against different drug-resistant parasite strains with potentially improved selectivity towards the parasite compared to mammalian cells. We also confirmed that the activity of the PROTACs in the parasite is reliant on the entire molecule and not only its individual ligand components. We also found that the cis-isomers of the PROTACs have improved or similar activity against the parasite, indicating that the interaction with the E3 ligase in the parasite is not stereochemically driven. Co-treatment of the parasites with the PROTACs and a proteasome inhibitor, epoxomicin, did not affect the activity of MZ1 while VZ185 was adversely affected, indicating that the effect of the latter relies on active proteolysis. We determined if the biological action of VZ185 in the parasite was related to epigenetic mechanisms by studying the changes in the morphology of parasites treated with the PROTAC. We found that asexual blood stage parasites treated with VZ185, and cis-VZ185, altered the parasite's ability to produce daughter cells and inhibit haemoglobin metabolism. This study demonstrated that PROTACs could be used as potential antimalarial compounds and a tool to probe parasite biology. National Research Foundation (NRF) Biochemistry, Genetics and Microbiology (BGM) MSc (Biochemistry) Unrestricted Faculty of Natural and Agricultural Sciences SDG-03: Good health and well-being SDG-04: Quality education SDG-09: Industry, innovation and infrastructure 2025-01-28T10:09:48Z 2025-01-28T10:09:48Z 2025-05 2024-10-29 Dissertation * http://hdl.handle.net/2263/100338 10.25403/UPresearchdata.28269989 en © 2023 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. application/pdf University of Pretoria |
| spellingShingle | UCTD Sustainable Development Goals (SDGs) Plasmodium falciparum Malaria Targeted protein degradation Proteolysis-targeting chimera (PROTAC) Epigenetics Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites |
| title | Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites |
| title_full | Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites |
| title_fullStr | Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites |
| title_full_unstemmed | Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites |
| title_short | Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites |
| title_sort | proteolysis targeting chimeras as a novel strategy for targeting epigenetic mechanisms in plasmodium falciparum parasites |
| topic | UCTD Sustainable Development Goals (SDGs) Plasmodium falciparum Malaria Targeted protein degradation Proteolysis-targeting chimera (PROTAC) Epigenetics |
| url | http://hdl.handle.net/2263/100338 |