TY - JOUR
T1 - The dolabellane diterpene Dolabelladienetriol is a typical noncompetitive inhibitor of HIV-1 reverse transcriptase enzyme
AU - Cirne-Santos, Claudio Cesar
AU - Souza, Thiago Moreno L.
AU - Teixeira, Valéria L.
AU - Fontes, Carlos Frederico L.
AU - Rebello, Moacyr A.
AU - Castello-Branco, Luiz Roberto R.
AU - Abreu, Celina M.
AU - Tanuri, Amílcar
AU - Frugulhetti, Izabel C.P.P.
AU - Bou-Habib, Dumith Chequer
N1 - Funding Information:
We thank the Hemotherapy Service of the Hospital Clementino Fraga Filho (Federal University of Rio de Janeiro) for providing buffy coats. This work was supported by grants from PAPES/Fiocruz, CNPq, Faperj and CAPES. The antiretroviral atazanavir sulphate and the purified HIV-1 enzyme reverse transcriptase were obtained from NIH AIDS Research and Reference Reagent Program (Division of AIDS, NIAID, NIH, Bethesda, MD and Dr. Stuart Le Grice, respectively). C.C.C.-S is a Post-Doctoral fellow of the Laboratory of Clinical Immunology, Oswaldo Cruz Institute/Fiocruz and T.M.L.S is a PhD student of the Institute Medical Biochemistry Institute, Federal University of Rio de Janeiro, RJ, Brazil, and are supported, respectively, by CNPq and CAPES.
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - AIDS
KW - Diterpene
KW - Dolabelladienetriol
KW - HIV-1
KW - Reverse transcriptase
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UR - http://www.scopus.com/inward/citedby.url?scp=37549017330&partnerID=8YFLogxK
U2 - 10.1016/j.antiviral.2007.08.006
DO - 10.1016/j.antiviral.2007.08.006
M3 - Article
C2 - 17888523
AN - SCOPUS:37549017330
SN - 0166-3542
VL - 77
SP - 64
EP - 71
JO - Antiviral Research
JF - Antiviral Research
IS - 1
ER -