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.

Inhibition of HIV-1 Ribonuclease H activity by novel frangula-emodine derivatives

ESPOSITO, FRANCESCA;ZINZULA, LUCA;TRAMONTANO, ENZO
2009

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.
HIV-1; reverse transcriptase; RNAse H
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/88970
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 34
  • ???jsp.display-item.citation.isi??? 31
social impact