M.Sc. / Background: The continuous emergence of drug resistant strains of HIV as a result of errors made by reverse transcriptase coupled with undesirable side effects of available drugs, latency problems, cost etc, warrants the continuous search for new drug candidates. Chrysotherapy which is the use of gold compounds for the treatment of various ailments has been practiced since 2500 BC. The use of gold compounds such as auranofin for the treatment of rheumatoid arthritis has lead to remission of this disease. Gold compounds such as auranofin not only prevented the progression of arthritis but also increased the CD4+ count of an HIV positive patient who was not on antiretrovirals. These compounds have been implicated in the treatment of cancers, autoimmune diseases and microorganism infections. Objectives: In this work, novel gold compounds were evaluated with the aim of identifying lead compound(s) that can eventually serve as anti-HIV agents. Materials and Methods: Eleven gold (I) phosphine complexes, four of their corresponding ligands (compound without gold atom), and a gold (III) complex were tested for the ability to inhibit reverse transcriptase (RT) and protease (PR) in direct enzyme assays. Uptake of the compounds by host cells was evaluated with inductively coupled plasma atomic emission spectrometry (ICP-AES). Potential toxicity of the gold compounds was screened for by viability dyes and flow cytometry assays. To determine inhibition of whole virus by other mechanisms in addition to RT or PR, p24 production by infected cells was evaluated. Prior to all these analysis, stability of compounds in solution was determined by 31P nuclear magnetic resonance (NMR) and UV-visible spectroscopy. Results: The compounds were shown to be stable in solution over a one week period and were taken up by both continuous cell lines and primary cells. Eight of the gold compounds significantly inhibited HIV-1 reverse transcriptase at concentrations of 25 and 250 μM while four compounds and the four ligands did not. In a fluorogenic assay against HIV-1 PR, four of the gold compounds demonstrated inhibitory activity. The gold compounds were toxic to cells lines but not to primary cells. One of the complexes (EK231) significantly reduced p24 (p=0.0042) production at a concentration of 25 μM. Conclusion: Data provided here suggests that the therapeutic benefits of these gold containing compounds as potential HIV-1 reverse transcriptase and protease inhibitors should be considered.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uj/uj:8364 |
| Date | 07 May 2009 |
| Creators | Fonteh, Pascaline Nanga |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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