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Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues
Dissertation (MSc)--University of Pretoria, 2015.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2015
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| _version_ | 1867613600266321920 |
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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 | © 2015 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)--University of Pretoria, 2015. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/46152 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:38:42.927Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| 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:2263/46152 Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues Birkholtz, Lyn-Marie Barnard, Bernice UCTD Malaria Drug discovery Plasmidium Pollyamine Dissertation (MSc)--University of Pretoria, 2015. According to the World Health Organization, malaria has been classified as one of the three most important infectious diseases in Africa. The number of malaria cases is still on the increase in various countries, such as Rwanda and Zambia, which highlights the fragility of malaria control and the need to maintain and improve control programs. An innovative strategy for developing new antimalarial agents is through targeting epigenetic regulatory mechanisms in the malarial parasite, Plasmodium falciparum. Histone posttranslational modifications (PTMs) are factors contributing to epigenetic regulation in P. falciparum parasites. The epigenetic regulatory enzyme, Lysine-specific demethylase 1 (LSD1), has the ability to remove methyl groups from mono- and dimethylated lysine residues and is a regulator of gene expression through the modulation of chromatin structure. Polyamine analogues have been described as epi-drugs that target cell cycle development by blocking epigenetic control mechanisms in mammalian cells. A library of polyamine analogues were tested in cancer cells and found to specifically inhibit LSD1. In addition, these analogues were shown to have antiplasmodial activity against a drug-sensitive parasite strain, with IC50 values ranging from 88-100 nM but were metabolically unstable in vivo. In an attempt to overcome this in vivo hurdle, the leading compound was fluorinated at four different positions and tested for improved antiplasmodial activity and selectivity towards the parasites. Furthermore, the effect of the compounds on epigenetic regulatory mechanisms, through inhibition of LSD1 activity, was investigated. The analogues showed inhibition of parasite proliferation at low nanomolar concentrations and were very selective towards the parasites with low resistance indices. The leading compound showed reversible cytotoxicity towards parasite proliferation in addition to inhibitory activity against LSD1 and therefore, epigenetic regulatory changes. The approach taken in this dissertation is novel as none of the currently available antimalarials target LSD1 and as such, adds valuable information to future perspectives for drug design. tm2015 Biochemistry MSc Unrestricted 2015-07-02T11:06:59Z 2015-07-02T11:06:59Z 2015/04/22 2015 Dissertation Barnard, B 2015, Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues, MSc Dissertation, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/46152> A2015 http://hdl.handle.net/2263/46152 en © 2015 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 Malaria Drug discovery Plasmidium Pollyamine Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues |
| title | Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues |
| title_full | Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues |
| title_fullStr | Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues |
| title_full_unstemmed | Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues |
| title_short | Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues |
| title_sort | inhibition of lysine specific demethylase 1 as an antimalarial target by polyamine analogues |
| topic | UCTD Malaria Drug discovery Plasmidium Pollyamine |
| url | http://hdl.handle.net/2263/46152 |