The evaluation of gold-based compounds as potential inhibitors of HIV-1 replication.
| dc.contributor.author | Mphahlele, Morore Katlego | |
| dc.date.accessioned | 2012-01-17T09:23:45Z | |
| dc.date.available | 2012-01-17T09:23:45Z | |
| dc.date.issued | 2012-01-17 | |
| dc.description.abstract | Highly active antiretroviral therapy has successfully limited HIV-1 disease progression to AIDS, but is consistently compromised by the emergence and transmission of HIV-1 drug resistant strains. As a result, a continued search for novel anti-HIV-1 agents with improved pharmacological profiles has become fundamental. Chrysotherapy has been in use since the early 1920s in treatment of rheumatoid arthritis, and has since been investigated for various ailments including HIV/AIDS. This study evaluated 45 synthetic gold compounds for drug like properties using theoretical and experimental techniques with the aim of generating sufficient data to considerably aid the rational design of new anti-HIV agents. Theoretical techniques applied included the Osiris Property Explorer and the Lipinski’s Rule of Five which assessed drug-likeness and bioavailability respectively. In vitro studies included aqueous solubility assays, cytotoxicity (PM1 cell lines and PBMCs) assays, antiviral assays in PBMCs, direct enzyme (RT and IN) inhibition, and the effect of serum protein binding and biological stability on antiviral efficacy. An overall low druglikeness score and an intermediate bioavailability were predicted by the Osiris Molecular Property Explorer. Low drug-likeness was suggested to be due to a high frequency of foreign fragments in the synthetic gold compounds, while their high molecular weight reduced bioavailability. In general gold compounds exhibited cytotoxicity properties and moderate aqueous solubility in vitro. Overall, the 45 synthetic gold compounds did not show activity against HIV-1 replication in vitro. Seven compounds (AB05-AB11) exhibited direct HIV-1 RT inhibition, and compounds AB39 and AB04 demonstrated moderate direct HIV-1 IN inhibition, but this activity was abrogated in PBMC inhibition assays. Serum binding, compound stability and cytotoxicity were all implicated in the lack of HIV-1 inhibition in PBMCs. To this end, data obtained was sufficient to aid in the future rational design of second generation HIV RT and IN inhibitors with acceptable pharmacological properties. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10539/11030 | |
| dc.language.iso | en | en_US |
| dc.subject.mesh | Virus Replication | en-US |
| dc.subject.mesh | HIV-1 | en-US |
| dc.title | The evaluation of gold-based compounds as potential inhibitors of HIV-1 replication. | en_US |
| dc.type | Thesis | en_US |
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