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Nucleic Acids Research 2005 33(4):1249-1256; doi:10.1093/nar/gki268
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Published online 1 March 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

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

Scott R. Budihas, Inna Gorshkova1, Sergei Gaidamakov2, Antony Wamiru3,4, Marion K. Bona4, Michael A. Parniak5, Robert J. Crouch2, James B. McMahon3, John A. Beutler3 and Stuart F. J. Le Grice*

Resistance Mechanisms Laboratory, HIV Drug Resistance Program, National Cancer Institute at Frederick Frederick, MD 21702, USA 1Protein Biophysics Resource, Division of Bioengineering and Physical Sciences, National Institutes of Health Bethesda, MD 20892, USA 2Laboratory of Molecular Genetics, National Institute of Child Health and Human Development Bethesda, MD 20892, USA 3Molecular Targets Development Program, National Cancer Institute at Frederick Frederick, MD 21702, USA 4SAIC-Frederick, Frederick MD 21702, USA 5Division of Infectious Diseases, School of Medicine, University of Pittsburgh Pittsburgh, PA 15213, USA

*To whom correspondence should be addressed. Tel: +1 301 846 5256; Fax: +1 301 846 6013; Email: slegrice{at}ncifcrf.gov

Received January 11, 2005. Revised February 7, 2005. Accepted February 7, 2005.

High-throughput screening of a National Cancer Institute library of pure natural products identified the hydroxylated tropolone derivatives ß-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). ß-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 ß-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 ß-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 ß-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.


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