title: Modification of HIV-1 reverse transcriptase and integrase activity by gold(III) complexes in direct biochemical assays.
abstract: 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 KAuCl(4) and HAuCl(4) yielded sub-micromolar IC(50)'s of 0.947 and 0.983μM in the direct HIV-1 RT assay, respectively, while IC(50)'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 <5.95). Taken together, the findings of this study demonstrate that gold(III) complexes modify HIV-1 enzyme activity in direct biochemical assays, most likely through protein oxidation.
authors: Biomed, Advanced Materials Division, Mintek, Private Bag X3015, Randburg 2125, Johannesburg, South Africa.
authors: Morore
authors: M
authors: Mphahlele
authors: Maria
authors: M
authors: Papathanasopoulos
authors: Maria Agostina
authors: MA
authors: Cinellu
authors: Mabel
authors: M
authors: Coyanis
authors: Salerwe
authors: S
authors: Mosebi
authors: Telisha
authors: T
authors: Traut
authors: Refilwe
authors: R
authors: Modise
authors: Judy
authors: J
authors: Coates
authors: Raymond
authors: R
authors: Hewer
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D006046:Gold / Q000737:chemistry*; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D019428:HIV Integrase Inhibitors; D018894:Reverse Transcriptase Inhibitors; D006046:Gold; D019427:HIV Integrase; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C514801:p31 integrase protein, Human immunodeficiency virus 1