STUDIES ON THE INHIBITION OF POLYHYDROXYLATED AROMATIC COMPOUNDS AGAINST HIV-1 INTEGRASE

AIMThree 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. METHODSELISA 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. RESULTSCompound NQ-2 was found to inhibit HIV-1 integrase with the IC₅₀ of 78.5 μmol·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 μmol·L^-1. The IC₅₀s of NQ-2 and NQ-3 to inhibit the 3′-pro+assembly activity of integrase were 96.94 μmol·L^-1 and 8.48 μmol·L^-1; to inhibit assembly activity were 168 and 6.9 μmol·L^-1 and to inhibit strand-transfer activity were 49.8 and 1.1 μmol·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. CONCLUSIONNaphthoquinone 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.