The dolabellane diterpene Dolabelladienetriol is a typical noncompetitive inhibitor of HIV-1 reverse transcriptase enzyme

Claudio Cesar Cirne-Santos, Thiago Moreno L. Souza, Valéria L. Teixeira, Carlos Frederico L. Fontes, Moacyr A. Rebello, Luiz Roberto R. Castello-Branco, Celina M. Abreu, Amílcar Tanuri, Izabel C.P.P. Frugulhetti, Dumith Chequer Bou-Habib

Research output: Contribution to journalArticlepeer-review

Abstract

We recently described that a dollabelane diterpene isolated from the marine algae Dictyota pfaffii (Dolabelladienetriol) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and HIV-1 replication in primary cells. Based on these findings, we investigated additional antiretroviral properties of Dolabelladienetriol. Here, we describe that Dolabelladienetriol blocked the synthesis and integration of HIV-1 provirus and completely abrogated viral replication in primary cells. Also, studies of kinetic mode of action revealed that the Dolabelladienetriol is a nonnucleoside RT inhibitor (NNRTI), acting as a noncompetitive inhibitor, with a Ki value equal to 7.2 μM. To assess whether Dolabelladienetriol could potentiate the anti-HIV-1 effects of other HIV-1 inhibitors, HIV-1-infected cells were treated with Dolabelladienetriol at its EC50 dose plus sub-optimal concentrations of classical antiretrovirals. Dolabelladienetriol provided an additive effect with the nucleoside RT inhibitor AZT, and a synergistic effect with the protease inhibitor atazanavir sulphate. There was no increment of the anti-HIV-1 effect resulting from the combination between Dolabelladienetriol and the NNRTI nevirapine. Using a large panel of HIV-1 isolates harboring NNRTI resistance mutations, we found no cross-resistance between Dolabelladienetriol and clinical available NNRTIs. Thus, Dolabelladienetriol is an NNRTI, with potent activity against HIV-1 isolates carrying common NNRTI-associated resistance mutations. Dolabelladienetriol may be considered as a potential new agent for anti-HIV-1 therapy.

Original languageEnglish (US)
Pages (from-to)64-71
Number of pages8
JournalAntiviral Research
Volume77
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

Keywords

  • AIDS
  • Diterpene
  • Dolabelladienetriol
  • HIV-1
  • Reverse transcriptase

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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