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Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors
Dissertation (MSc (Biochemistry))--University of Pretoria, 2021.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2021
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| _version_ | 1867613526094249984 |
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| access_status_str | Open Access |
| author2 | Gama, Ntombenhle Hlengiwe |
| author_browse | Gama, Ntombenhle Hlengiwe |
| author_facet | Gama, Ntombenhle Hlengiwe |
| collection | Thesis |
| dc_rights_str_mv | © 2019 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, 2021. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/78344 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:37:32.711Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| 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:2263/78344 Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors Gama, Ntombenhle Hlengiwe bmfputterill@gmail.com Meyer, Debra Putterill, Brandon Marquand Fraser UCTD Human immunodeficiency virus (HIV) Dissertation (MSc (Biochemistry))--University of Pretoria, 2021. Background: The human immunodeficiency virus (HIV) is the cause of the acquired immunodeficiency syndrome (AIDS). AIDS is fatal if not treated appropriately. Although there are treatment options for the infection, there are many problems associated with it, including non-compliance to prescribed treatments due to toxicity and side effects, leading to drug resistance. There is therefore a need to develop novel drugs that are less toxic. This study contributes to the fight against HIV/AIDS by recommending new metallodrugs able to address the shortcomings of existing treatments. Metals have previously demonstrated potential in targeting HIV-1, mostly with activity against the enzymes reverse transcriptase and protease. The current study investigated the effects of metal-based complexes against viral entry into host cells. Methods: Three metal-based complexes; Aryl-1H-1,2,3- triazole-based cyclometalated Ruthenium (II) complex (A), Aryl-1H-1,2,3- triazole-based cyclometalated Iridium (III) complex (B) and Aryl-1H-1,2,3- triazole-based cyclometalated Osmium (II) complexes (C) were investigated for potential HIV entry inhibition and their activity was compared to that of the ligand which did not contain the metal component. The study analysed the toxicity of the complexes in TZM-bl cells and Peripheral blood mononuclear cells (PBMCs). Three pseudo-viruses (CAP 210, Du 156 and Q 23) were created using transformation and transfection methods and a luciferase reporter gene assay was used to analyse the inhibitory effects of the complexes on the pseudo-virus infection of TZM bl cells. Active complexes were further analysed for a potential mechanism of action through in silico docking. Results and discussion: The complexes were found to have lower CC50 values in PBMCs compared to TZM-bl cells. In both cell lines, B had the lowest CC50 value, which can be attributed to the increased hydrolysis of the chloride atom bound to the iridium as well as the increased uptake into the cells. Based on the luciferase reporter gene assay all three of the metal-based complexes had inhibition of viral infection with IC50 values ranging from 5.34 – 7.41 µM for A, 2.35 – 8.09 µM for B and 2.59 to 4.18 µM for C. The ligand was only analysed for any inhibitory activity on one of the pseudo-viruses (Du 156) and was found to have no significant inhibition. Selectivity index (SI) values indicated the complexes were effective at non-toxic concentrations with values ranging from 1.61 – 4.56 for B, 3.29 – 4.56 for A and 7.03 – 11.26 for C. In silico docking analysis of the proteins involved in viral entry indicated that inhibition possibly occurred through interaction with the CCR5 co-receptor, as the docking scores for this protein were the most negative indicative of favourable interactions between proteins and ligands. Conclusion: The metal-based complexes showed inhibition with IC50 values in the low micromolar range, while the ligand had no statistically significant inhibition. This suggests that the presence of the metal ion enhances viral inhibition. Furthermore, inhibition was through the interaction of the complexes with CCR5, in a manner similar to that of Maraviroc, a clinically utilized CCR5 inhibitor. This study identified novel metal-based HIV-1 entry inhibitors which were effective against HIV-1 subtype A and C at non-toxic concentrations. Biochemistry MSc (Biochemistry) Unrestricted 2021-02-10T06:18:05Z 2021-02-10T06:18:05Z 2021 2021 Dissertation * http://hdl.handle.net/2263/78344 en © 2019 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 Human immunodeficiency virus (HIV) Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors |
| title | Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors |
| title_full | Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors |
| title_fullStr | Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors |
| title_full_unstemmed | Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors |
| title_short | Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 entry inhibitors |
| title_sort | triazolyl ru ii os ii and ir iii complexes as potential hiv 1 entry inhibitors |
| topic | UCTD Human immunodeficiency virus (HIV) |
| url | http://hdl.handle.net/2263/78344 |