Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones

Abstract

High-throughput screening of a National Cancer Institute library of pure natural products identified the hydroxylated tropolone derivatives β-thujaplicinol (2,7-dihydroxy-4-1(methylethyl)-2,4,6-cycloheptatrien-1-one) and manicol (1,2,3,4-tetrahydro-5-7-dihydroxy-9-methyl-2-(1-methylethenyl)-6H-benzocyclohepten-6-one) as potent and selective inhibitors of the ribonuclease H (RNase H) activity of human immunodeficiency virus-type 1 reverse transcriptase (HIV-1 RT). β-Thujaplicinol inhibited HIV-1 RNase H in vitro with an IC50 of 0.2 μM, while the IC50 for Escherichia coli and human RNases H was 50 μM and 5.7 μM, respectively. In contrast, the related tropolone analog β-thujaplicin (2-hydroxy-4-(methylethyl)-2,4,6-cycloheptatrien-1-one), which lacks the 7-OH group of the heptatriene ring, was inactive, while manicol, which possesses a 7-OH group, inhibited HIV-1 and E.coli RNases H with IC50 = 1.5 μM and 40 μM, respectively. Such a result highlights the importance of the 2,7-dihydroxy function of these tropolone analogs, possibly through a role in metal chelation at the RNase H active site. Inhibition of HIV-2 RT-associated RNase H indirectly indicates that these compounds do not occupy the nonnucleoside inhibitor-binding pocket in the vicinity of the DNA polymerase domain. Both β-thujaplicinol and manicol failed to inhibit DNA-dependent DNA polymerase activity of HIV-1 RT at a concentration of 50 μM, suggesting that they are specific for the C-terminal RNase H domain, while surface plasmon resonance studies indicated that the inhibition was not due to intercalation of the analog into the nucleic acid substrate. Finally, we have demonstrated synergy between β-thujaplicinol and calanolide A, a nonnucleoside inhibitor of HIV-1 RT, raising the possibility that both enzymatic activities of HIV-1 RT can be simultaneously targeted.

In vitro and in vivo antimalarial activity of puberulic acid and its new analogs, viticolins A–C, produced by Penicillium sp. FKI-4410

“…16 In general, the natural and synthetic tropolones have been reported to show antibacterial, antifungal, insecticidal, antiviral and antitumor activities, as well as inhibiting enzymes such as aminoglycoside-2 00 -O-adenyltransferase, 17 metalloprotease 18 and HIV-1 reverse transcriptase-associated ribonuclease H. 19 The inhibitory mechanisms of tropolones were thought to reflect their ability to form a complex with divalent cations. 20 Among these compounds, hinokitiol and its related synthetic derivatives have been reported to show antimalarial activity, whereas the synthetic benzotropolone derivatives 15,21,22 and a dihydrotroplone antibiotic, cordytropolone, 23 have also been reported to show moderate or weak antimalarial activities in vitro.…”

Resistance and Tolerance to Tropodithietic Acid, an Antimicrobial in Aquaculture, Is Hard To Select

“…It is antibacterial against several bacteria, including Escherichia coli and Pseudomonas aeruginosa (3,26,48). Tropolones with side groups other than a disulfide are also known to be antibacterial (32,33) and display antifungal and antiviral activities (7,26).…”

Tissue-Based Model of HCV Replication as a Replacement for Animal Models in Drug Testing

“…Tropolones possess multiple biological activities: antiviral, antimicrobial, and cytotoxic effects on various human tumour cell lines [75][76][77] . They may also exert an insecticidal as well as a metalloprotease inhibitory effects [78].…”