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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/11030 |
| Date | 17 January 2012 |
| Creators | Mphahlele, Morore Katlego |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf, application/pdf |
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