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多拉贝拉烷二萜类化合物多拉贝拉二烯三醇是HIV-1逆转录酶的典型非竞争性抑制剂。

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

作者信息

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

机构信息

Laboratório de Imunologia Clínica, Departamento de Imunologia, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, RJ 21045-900, Brazil.

出版信息

Antiviral Res. 2008 Jan;77(1):64-71. doi: 10.1016/j.antiviral.2007.08.006. Epub 2007 Sep 6.

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 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.

摘要

我们最近报道,从海洋藻类Pfaffii网地藻中分离出的一种多拉贝拉烷二萜(多拉贝拉二烯三醇)可抑制人类免疫缺陷病毒1型(HIV-1)的逆转录酶(RT),并抑制HIV-1在原代细胞中的复制。基于这些发现,我们研究了多拉贝拉二烯三醇的其他抗逆转录病毒特性。在此,我们描述多拉贝拉二烯三醇可阻断HIV-1前病毒的合成与整合,并完全消除其在原代细胞中的病毒复制。此外,作用动力学模式研究表明,多拉贝拉二烯三醇是一种非核苷类逆转录酶抑制剂(NNRTI),作为非竞争性抑制剂,其抑制常数(K(i))值等于7.2微摩尔。为评估多拉贝拉二烯三醇是否能增强其他HIV-1抑制剂的抗HIV-1作用,用其半数有效浓度(EC(50))剂量联合次优浓度的经典抗逆转录病毒药物处理HIV-1感染细胞。多拉贝拉二烯三醇与核苷类逆转录酶抑制剂齐多夫定(AZT)产生相加作用,与蛋白酶抑制剂硫酸阿扎那韦产生协同作用。多拉贝拉二烯三醇与非核苷类逆转录酶抑制剂奈韦拉平联合使用未增强抗HIV-1作用。使用大量携带非核苷类逆转录酶抑制剂耐药突变的HIV-1分离株,我们发现多拉贝拉二烯三醇与临床可用的非核苷类逆转录酶抑制剂之间无交叉耐药。因此,多拉贝拉二烯三醇是一种非核苷类逆转录酶抑制剂,对携带常见非核苷类逆转录酶抑制剂相关耐药突变的HIV-1分离株具有强效活性。多拉贝拉二烯三醇可被视为抗HIV-1治疗的潜在新药。

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