Abstract
The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) activity hydrolyzes the RNA component of the viral heteroduplex RNA:DNA replication intermediate. Even though this function is essential for viral replication, until now only very few compounds have been reported to inhibit it. Anthraquinones are common secondary metabolites which have diverse biological activities. In particular, some of them have been reported to inhibit the HIV-1 RT polymerase and integrase activities in biochemical assays. Given the structural similarities between integrase and RNase H proteins, we synthesized a series of frangula-emodine derivatives and showed that the introduction of a bromine atom in position 7 of the anthraquinone structure leads to derivatives which are able to inhibit both HIV-1 polymerase and RNase H functions at micromolar concentrations. Mechanism of action studies performed on the 7-brom-6-O-phenacyl-1,8- dihydroxy-3-methyl anthraquinone (K67) showed that this compound is a non-competitive inhibitor of the RNase H function and that it binds to a site which is not overlapping to the non-nucleoside RT inhibitors binding site. This study demonstrates that anthraquinone derivatives may be a scaffold to be further developed to obtain selective HIV-1 RNase H inhibitors and represent a new step toward the identification of new anti-RT agents.
Keywords: HIV-1, Ribonuclease H, RNase H, Drug discovery, Anthraquinones, Enzyme inhibition, Reverse transcriptase, RT
Medicinal Chemistry
Title: Inhibition of HIV-1 Ribonuclease H Activity by Novel Frangula-Emodine Derivatives
Volume: 5 Issue: 5
Author(s): Kharlamova Tatyana, Esposito Francesca, Zinzula Luca, Floris Giovanni, Cheng Yung-Chi, E. Dutschman Ginger and Tramontano Enzo
Affiliation:
Keywords: HIV-1, Ribonuclease H, RNase H, Drug discovery, Anthraquinones, Enzyme inhibition, Reverse transcriptase, RT
Abstract: The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) activity hydrolyzes the RNA component of the viral heteroduplex RNA:DNA replication intermediate. Even though this function is essential for viral replication, until now only very few compounds have been reported to inhibit it. Anthraquinones are common secondary metabolites which have diverse biological activities. In particular, some of them have been reported to inhibit the HIV-1 RT polymerase and integrase activities in biochemical assays. Given the structural similarities between integrase and RNase H proteins, we synthesized a series of frangula-emodine derivatives and showed that the introduction of a bromine atom in position 7 of the anthraquinone structure leads to derivatives which are able to inhibit both HIV-1 polymerase and RNase H functions at micromolar concentrations. Mechanism of action studies performed on the 7-brom-6-O-phenacyl-1,8- dihydroxy-3-methyl anthraquinone (K67) showed that this compound is a non-competitive inhibitor of the RNase H function and that it binds to a site which is not overlapping to the non-nucleoside RT inhibitors binding site. This study demonstrates that anthraquinone derivatives may be a scaffold to be further developed to obtain selective HIV-1 RNase H inhibitors and represent a new step toward the identification of new anti-RT agents.
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Cite this article as:
Tatyana Kharlamova, Francesca Esposito, Luca Zinzula, Giovanni Floris, Yung-Chi Cheng, Ginger Dutschman E. and Enzo Tramontano, Inhibition of HIV-1 Ribonuclease H Activity by Novel Frangula-Emodine Derivatives, Medicinal Chemistry 2009; 5 (5) . https://dx.doi.org/10.2174/157340609789117840
DOI https://dx.doi.org/10.2174/157340609789117840 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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