Biomed, Advanced Materials Division, Mintek, Private Bag X3015, Randburg 2125, Johannesburg, South Africa.
Bioorg Med Chem. 2012 Jan 1;20(1):401-7. doi: 10.1016/j.bmc.2011.10.072. Epub 2011 Nov 3.
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.
金（I）和金（III）配合物以前曾被研究用于包括抗 HIV 药物在内的潜在的生物医学应用。一些金（III）配合物的氧化性在基于细胞的测定中产生了有充分文献记录的细胞毒性，但在直接生化测定中的影响尚未得到充分研究。在这项研究中，金（III）配合物在 HIV-1 逆转录酶和 HIV-1 整合酶生化测定中进行了评估。金（III）四氯化物 KAuCl(4)和 HAuCl(4)在直接 HIV-1 RT 测定中分别产生了 0.947 和 0.983μM 的亚微摩尔 IC(50)，而对于七个选定的金（III）配合物，IC(50)范围从 0.461 到 8.796μM。金（III）四氯化物也是整合酶酶活性的有效抑制剂，在 10μM 的单一剂量评估中获得了 >80%的抑制。在存在还原剂（10mM DTT）和针对 HIV-1 RT M184V 突变体的情况下，RT 抑制作用降低，而没有一种金（III）配合物在细胞抗病毒测定中是有效的抑制剂（SI 值 <5.95）。总之，这项研究的结果表明，金（III）配合物在直接生化测定中改变了 HIV-1 酶的活性，这很可能是通过蛋白质氧化。
