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Anti-Malarial Polymer-Peptide Conjugates
Thesis (PhD)--Stellenbosch University, 2014.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2015
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| _version_ | 1867613847221698560 |
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| access_status_str | Open Access |
| author | Reader, Paul William |
| author2 | Klumperman, Bert |
| author_browse | Klumperman, Bert Reader, Paul William |
| author_facet | Klumperman, Bert Reader, Paul William |
| author_sort | Reader, Paul William |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2014. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/95758 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:42:38.497Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/95758 Anti-Malarial Polymer-Peptide Conjugates Reader, Paul William Klumperman, Bert Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Malaria -- Drugs -- Administration Tyrocidines UCTD Polymerization Drugs --Targeting Thesis (PhD)--Stellenbosch University, 2014. ENGLISH ABSTRACT: The primary aim of this study was to investigate an amphiphilic polyvinylpyrrolidone (PVP)-based drug delivery system for the treatment of the Plasmodium falciparum strain of malaria, using a known anti-malarial cylic decapeptide, tyrothricin. A triazole-based reversible addition-fragmentation chain-transfer (RAFT) agent, comprising an acetal-based R-group and a xanthate-based Z-group was synthesised. α-Acetal, ω-xanthate heterotelechelic PVP was synthesised via RAFT polymerisation and it was shown that the polymerisation was adequately controlled. A one-pot orthogonal chain-end functionality deprotection strategy was developed and conditions were established to conjugate a model targeting ligand and a model drug linker to the α- and ω-chain-ends, respectively. A micellar drug delivery system was developed by conjugating the aggregation-prone tyrothricin to PVP, via its ω-chain-end functionality through an acid-labile linker. The α-chain-end functionality of the PVP was sparsely conjugated to a targeting ligand and to a fluorescent marker. In aqueous media, the conjugate exhibited self-assembly into micelles. The tyrothricin formed the core of the micelle, stabilised via the hydrophilic PVP, decorated with the targeting ligands and fluorescent marker. The conjugate was shown to inhibit chloroquine-resistant P. falciparum strains of malaria in picomolar concentrations with virtually no haemolysis observed; a 700-fold improvement of the IC50 over tyrothricin alone was observed. In addition, the conjugates were found to vaccinate the erythrocytes against re-infection. The drug delivery system appears to be a promising candidate for further investigation as a treatment against drug-resistant strains of malaria. AFRIKAANSE OPSOMMING: Die primêre doel van hierdie studie was om 'n amfifiliese polivinielpirolidoon (PVP)-gebaseerde medisyne-toedieningstelsel vir die behandeling van die Plasmodium falciparum stam van malaria te ondersoek deur gebruik te maak van 'n bekende anti-malaria sikliese dekapeptied, genaamd tyrotrisien. 'n Triasool-gebaseerde omkeerbare byvoeging-fragmentasie kettingoordrag (BFKO) agent is gesintetiseer wat bestaan het uit 'n asetal-gebaseerde R-groep en 'n xantaat-gebaseerde Z-groep. α-Asetal, ω-xantaat heterotelesheliese PVP is gesintetiseer deur BFKO gemedieerde-polimerisasie en daar is bevind dat die polimerisasie voldoende beheer is. 'n Een-pot ortogonale endketting funksionaliteitsontskerming strategie is ontwikkel en kondisies is bepaal om 'n model teiken ligand en 'n model medisyne aanhegter aan die α- en ω-endkettings, onderskeidelik, te voeg. ‘n Missel-gebaseerde medisyne-toedieningstelsel is ontwikkel deur konjugasie van die tyrotrisien, wat geneig is om te aggregeer, aan die PVP. Dit het geskied deur die ω-endketting funksionaliteit deur middel van 'n suur-sensitiewe aanhegter. Die α-endketting funksionaliteit van die PVP is yl gekonjugeer met 'n teiken ligand en fluoreserende merker. In ‘n watermedium het die gekonjugeerde molekules selfsamevoeging-eienskappe getoon om miselle te vorm. Die tyrotrisien het die kern van die miselle gevorm en is gestabiliseer deur die hidrofiliese PVP, versier met die teiken ligande en fluoreserende merker. Daar is bevind dat die gekonjugeerde molekules chloroquine-weerstandige P. falciparum stamme van malaria geïnhibeer het in picomolare konsentrasies met feitlik geen hemoliese waargeneem; 'n 700-voudige verbetering van die IC50 van tyrotrisien alleen is waargeneem. Daarbenewens is bevind dat die gekonjugeerde molekules die rooibloedselle teen herbesmetting ge-ent het. Die medisyne-toedieningstelsel blyk 'n belowende kandidaat te wees vir verdere ondersoek as 'n behandeling teen medisyne-weerstandige stamme van malaria. Doctoral 2015-01-13T11:46:39Z 2016-11-20T03:00:05Z 2014-12 Thesis http://hdl.handle.net/10019.1/95758 en_ZA Stellenbosch University 112 pages application/pdf application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Malaria -- Drugs -- Administration Tyrocidines UCTD Polymerization Drugs --Targeting Reader, Paul William Anti-Malarial Polymer-Peptide Conjugates |
| title | Anti-Malarial Polymer-Peptide Conjugates |
| title_full | Anti-Malarial Polymer-Peptide Conjugates |
| title_fullStr | Anti-Malarial Polymer-Peptide Conjugates |
| title_full_unstemmed | Anti-Malarial Polymer-Peptide Conjugates |
| title_short | Anti-Malarial Polymer-Peptide Conjugates |
| title_sort | anti malarial polymer peptide conjugates |
| topic | Malaria -- Drugs -- Administration Tyrocidines UCTD Polymerization Drugs --Targeting |
| url | http://hdl.handle.net/10019.1/95758 |
| work_keys_str_mv | AT readerpaulwilliam antimalarialpolymerpeptideconjugates |