Modification of HIV-1 reverse transcriptase and integrase activity by gold(III) complexes in direct biochemical assays

• Published in: Bioorganic & medicinal chemistry 2012-01, Vol.20 (1), p.401-407
• Main Authors: Mphahlele, Morore, Papathanasopoulos, Maria, Cinellu, Maria Agostina, Coyanis, Mabel, Mosebi, Salerwe, Traut, Telisha, Modise, Refilwe, Coates, Judy, Hewer, Raymond
• Format: Article
• Language: English
• Subjects: antiretroviral agents; Binding Sites; Biological and medical sciences; Computer Simulation; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Dithiothreitol; Enzymatic activity; enzyme activity; gold; Gold - chemistry; Gold complexes; HIV Integrase - chemistry; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 reverse transcriptase; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; inhibitory concentration 50; Integrase; Leukocytes, Mononuclear - drug effects; Medical sciences; mutants; Oxidation; Pharmacology. Drug treatments; Reducing agents; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Toxicity
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.10.072

Schematic model of HIV-1 reverse transcriptase (RT) illustrating the positions of cysteine residues (in yellow) and methionine residues (in orange). In this manuscript, gold(III) compounds are shown to reduce HIV-1 RT activity, potentially though the oxidation of these residues. Gold(I) and gold(III) complexes have been previously investigated for potential biomedical applications including as anti-HIV agents. The oxidising nature of some gold(III) complexes yields well-documented cellular toxicity in cell-based assays but the effect in direct biochemical assays has not been fully investigated. In this study, gold(III) complexes were evaluated in HIV-1 reverse transcriptase and HIV-1 integrase biochemical assays. The gold(III) tetrachlorides KAuCl4 and HAuCl4 yielded sub-micromolar IC50’s of 0.947 and 0.983μM in the direct HIV-1 RT assay, respectively, while IC50’s ranging from 0.461 to 8.796μM were obtained for seven selected gold(III) complexes. The gold(III) tetrachlorides were also effective inhibitors of integrase enzymatic activity with >80% inhibition obtained at a single dose evaluation of 10μM. RT inhibition was decreased in the presence of a reducing agent (10mM DTT) and against the M184V HIV-1 RT mutant, while none of the gold(III) complexes were effective inhibitors in cell-based antiviral assays (SI values