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PVP bioconjugates of membrane disruptive peptides
Thesis (PhD)--Stellenbosch University, 2020.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2020
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| _version_ | 1867614041448382464 |
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| access_status_str | Open Access |
| author | Jokonya, Simbarashe |
| author2 | Klumperman, Bert |
| author_browse | Jokonya, Simbarashe Klumperman, Bert |
| author_facet | Klumperman, Bert Jokonya, Simbarashe |
| author_sort | Jokonya, Simbarashe |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2020. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/108343 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:45:43.568Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2020 |
| publishDateRange | 2020 |
| publishDateSort | 2020 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/108343 PVP bioconjugates of membrane disruptive peptides Jokonya, Simbarashe Klumperman, Bert Rautenbach, Marina Pfukwa, Rueben Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Bioconjugates Water-soluble polymers Drug delivery systems Tyrocidines UCTD Thesis (PhD)--Stellenbosch University, 2020. ENGLISH ABSTRACT:This study describes the development of poly(N-vinylpyrrolidone) (PVP) based membrane disruptive peptide bioconjugates capable of delivery to prostate specific membrane antigen (PSMA)-positive cells, red blood cells (RBCs) infected by malaria and other low pH physiological targets. An acetal functional, triazole based xanthate reversible addition-fragmentation chain-transfer (RAFT) agent was synthesised and subsequently employed in the polymerisation of N-vinylpyrrolidone (NVP) to yield heterotelechelic PVP with good control over molecular weight, dispersity and chain-end retention. The resultant α-acetal, ω-xanthate, heterotelechelic PVP underwent orthogonal deprotection of chain-ends to facilitate post polymerisation modifications as well as bioconjugation. A PSMA specific glutamate urea targeting ligand was synthesised from L-lysine. The PSMA ligand, along with an N-terminal functional – GRSKGT, malaria parasite specific targeting ligand and a fluorescent marker were conjugated to the α-chain end of heterotelechelic PVP via Schiff base formation and reductive amination. Tyrothricin cyclic decapeptides were obtained from cultures of Bacillus aneurinolyticus and purified to give a tyrocidine decapeptide preparation. Tyrocidine was acrylate modified and conjugated to the ω-chain end of heterotelechelic PVP via thiol-ene Michael addition. The resultant PVP-tyrocidine conjugates were capable of self-assembling in aqueous media, into aggregates whose sizes and morphologies were determined by dynamic light scattering (DLS) and by transmission electron microscopy (TEM). Studies on Plasmodium falciparum inhibition indicated that PVP-tyrocidine conjugates inhibited the NF54 strains at nanomolar concentrations. Conjugates decorated with a malaria specific ligand were found to be more active as indicated by the low inhibitory concentrations (IC50). Higher molecular weight conjugates resulted in less haemolysis as indicated by the higher haemolytic concentrations (HC50). Studies on glioma cells indicated that the fluorescently tagged PVP-tyrocidine conjugates induced propidium iodide (PI) response, and DNA binding upon entry into the cell cytosol. However, there was no evidence of organelle co-localisation of the fluorescence signal with lysotracker. Activity and targeting efficiency studies on PSMA-positive cells are still on-going, thus, the pending results could not be included due to time constraints. AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar. Doctoral 2020-01-16T10:06:40Z 2020-04-28T15:10:25Z 2020-01-16T10:06:40Z 2020-04-28T15:10:25Z 2020-01 Thesis http://hdl.handle.net/10019.1/108343 en_ZA Stellenbosch University xv, 124 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Bioconjugates Water-soluble polymers Drug delivery systems Tyrocidines UCTD Jokonya, Simbarashe PVP bioconjugates of membrane disruptive peptides |
| title | PVP bioconjugates of membrane disruptive peptides |
| title_full | PVP bioconjugates of membrane disruptive peptides |
| title_fullStr | PVP bioconjugates of membrane disruptive peptides |
| title_full_unstemmed | PVP bioconjugates of membrane disruptive peptides |
| title_short | PVP bioconjugates of membrane disruptive peptides |
| title_sort | pvp bioconjugates of membrane disruptive peptides |
| topic | Bioconjugates Water-soluble polymers Drug delivery systems Tyrocidines UCTD |
| url | http://hdl.handle.net/10019.1/108343 |
| work_keys_str_mv | AT jokonyasimbarashe pvpbioconjugatesofmembranedisruptivepeptides |