Inhibitory effects of quinones on RNase H activity associated with HIV-1 reverse transcriptase.
In an effort to develop new drugs preventing the growth of human immunodeficiency virus (HIV), we developed an in vitro assay method of ribonuclease H (RNase H) activity associated with reverse transcriptase (RT) from HIV-1. Some naphthoquinones, such as 1,4-naphthoquinone (1), vitamin K(3) (2), juglone (3) and plumbagin (6), moderately inhibited RNase H activity, and others, including naphthazarin (5) and shikonins (8-9, 18-23), showed weak inhibition. Diterpenoid quinones, tanshinones (24-28), had also moderate inhibition against RNase H activity. Of these quinones, compound 1 showed the most potent inhibition on RNase H activity with a 50% inhibitory concentration (IC(50)) of 9.5 microM, together with moderate inhibition against RNA-dependent and DNA-dependent DNA polymerase (RDDP and DDDP) activities with IC(50) values of 69 and 36 microM, respectively. Compounds 3 and 5 showed significant inhibition against RDDP (IC(50) = 8 and 10 microM, respectively) and DDDP (IC(50) = 5 and 7 microM, respectively) activities. The structure-activity relationship of the naphthoquinones suggested that non-hydroxylated naphthoquinones (1 and 2) showed significant inhibition of RNase H activity, whereas 5-hydroxylated naphthoquinones (3 and 5) showed potent inhibition against RDDP and DDDP activities.
Min
Byung-Sun
BS
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Miyashiro
Hirotsugu
H
Hattori
Masao
M
D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D008517:Phytotherapy; D011809:Quinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016914:Ribonuclease H / Q000187:drug effects*
D017320:HIV Protease Inhibitors; D009285:Naphthoquinones; D011809:Quinones; C016101:shikonin; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H