Studies on the inhibition of polyhydroxylated aromatic compounds against HIV-1 integrase / 药学学报

ABSTRACT

<p><b>AIM</b>Three major enzymes of HIV-1, reverse transcriptase (RT), protease (PR), and integrase (IN), are important targets for anti-HIV drugs. Nine RT and five PR inhibitors have been effectively used in treatment of AIDS patients. In order to find active integrase inhibitors, twenty polyhydroxylated aromatic compounds were tested.</p><p><b>METHODS</b>ELISA method was used to test the integrase activity. The synthesized donor substrate oligonucleotide representing the HIV-1 U5LTR was immobilized onto Covalink polystyrene microtiter plates, and a synthesized biotinlated 20 bp oligonucleotide was used as the target substrate. The products were detected and quantified by a colorimetric avidin-linked alkaline phosphatase reporter system.</p><p><b>RESULTS</b>Compound NQ-2 was found to inhibit HIV-1 integrase with the IC50 of 78.5 mumol.L-1 by ELISA method. Its novel analogue NQ-3 was found to be 2 fold more potent on HIV intrgrase than NQ-2, IC50 was 37.2 mumol.L-1. The IC50s of NQ-2 and NQ-3 to inhibit the 3'-pro + assembly activity of integrase were 96.94 mumol.L-1 and 8.48 mumol.L-1; to inhibit assembly activity were 168 and 6.9 mumol.L-1 and to inhibit strand-transfer activity were 49.8 and 1.1 mumol.L-1, respectively. Compound NQ-2 mostly inhibited the strand transfer activity of HIV-1 integrase. Compound NQ-3 inhibited both the assembly and strand-transfer with high activities.</p><p><b>CONCLUSION</b>Naphthoquinone compound NQ-3 was found to be a novel HIV integrase inhibitor which warrants further study. Uncoupled ELISA HIV integrase assay is shown to be useful to screen HIV-1 integrase inhibitors.</p>