[Studies on the inhibition of polyhydroxylated aromatic compounds against HIV-1 integrase].
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Guo
Zhi-min
ZM
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Chen
Hong-shan
HS
Wang
Lin
L
D003374:Coumarins / Q000494:pharmacology; D019427:HIV Integrase / Q000187:drug effects / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D009285:Naphthoquinones / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
D003374:Coumarins; D019428:HIV Integrase Inhibitors; D009285:Naphthoquinones; D011084:Polycyclic Aromatic Hydrocarbons; D013267:Stilbenes; D019427:HIV Integrase; D000077185:Resveratrol