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

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