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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Inhibition of HIV-1 Ribonuclease H Activity by Novel Frangula-Emodine Derivatives

Author(s): Kharlamova Tatyana, Esposito Francesca, Zinzula Luca, Floris Giovanni, Cheng Yung-Chi, E. Dutschman Ginger and Tramontano Enzo

Volume 5 , Issue 5 , 2009

Page: [398 - 410] Pages: 13

DOI: 10.2174/157340609789117840

Price: $65


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

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