The dolabellane diterpene Dolabelladienetriol is a typical noncompetitive inhibitor of HIV-1 reverse transcriptase enzyme.
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 K(i) value equal to 7.2 microM. 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 EC(50) 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.
Cirne-Santos
Claudio Cesar
CC
Laboratório de Imunologia Clínica, Departamento de Imunologia, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, RJ 21045-900, Brazil.
Souza
Thiago Moreno L
TM
Teixeira
Valéria L
VL
Fontes
Carlos Frederico L
CF
Rebello
Moacyr A
MA
Castello-Branco
Luiz Roberto R
LR
Abreu
Celina M
CM
Tanuri
Amílcar
A
Frugulhetti
Izabel C P P
IC
Bou-Habib
Dumith Chequer
DC
D019380:Anti-HIV Agents / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology*; D009154:Mutation; D011533:Proviruses / Q000187:drug effects / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016662:Virus Integration / Q000187:drug effects
D019380:Anti-HIV Agents; D004224:Diterpenes; D004338:Drug Combinations; D018894:Reverse Transcriptase Inhibitors; C115566:dolabellane