Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif*
Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif*
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开发 HIV-1 Tat 富含精氨酸基序的功能性主链环状模拟物*
DOI：
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发表时间：
2000
影响因子：
4.8
通讯作者：
C. Gilon
中科院分区：
文献类型：
--
作者：
A. Friedler;D. Friedler;N. Luedtke;Y. Tor;A. Loyter;C. Gilon
我们使用主链环状蛋白质模拟方法来开发在功能上模仿 HIV-1 Tat 蛋白的富含精氨酸基序 (ARM) 的肽。该共有序列既充当核定位信号 (NLS) 又充当 RNA 结合域。基于Tat的NMR结构，我们设计并合成了骨架环状ARM模拟肽库。筛选肽在透化细胞中介导相应 BSA 缀合物入核的能力。一种名为“Tat11”的肽显示出活跃的 NLS 特性。发现 Tat11-BSA 的核输入通过 Tat-NLS 使用的相同独特途径进行，而不是通过 SV40-NLS 使用的共同输入 α 途径进行。大多数 Tat 衍生的骨架环肽显示出选择性抑制活性，这通过 Tat-NLS 而不是 SV40-NLS 介导的核输入抑制得到证明。 Tat-ARM 衍生肽，包括 Tat-11，也抑制 HIV-1 Rev-ARM 与其相应 RNA 元件（Rev 响应元件）的结合，抑制常数为 5 nm。在这里，我们首次展示了（a）蛋白质序列的功能模拟物，它激活核输入受体和（b）具有双重功能的蛋白质序列模拟物。 Tat11 是一种先导化合物，可通过双重机制抑制 HIV-1 生命周期：抑制核输入和 RNA 结合。
We have used the backbone cyclic proteinomimetics approach to develop peptides that functionally mimic the arginine-rich motif (ARM) of the HIV-1 Tat protein. This consensus sequence serves both as a nuclear localization signal (NLS) and as an RNA binding domain. Based on the NMR structure of Tat, we have designed and synthesized a backbone cyclic ARM mimetic peptide library. The peptides were screened for their ability to mediate nuclear import of the corresponding BSA conjugates in permeabilized cells. One peptide, designated “Tat11,” displayed active NLS properties. Nuclear import of Tat11-BSA was found to proceed by the same distinct pathway used by the Tat-NLS and not by the common importin α pathway, which is used by the SV40-NLS. Most of the Tat-derived backbone cyclic peptides display selective inhibitory activity as demonstrated by the inhibition of the nuclear import mediated by the Tat-NLS and not by the SV40-NLS. The Tat-ARM-derived peptides, including Tat-11, also inhibited binding of the HIV-1 Rev-ARM to its corresponding RNA element (Rev response element) with inhibition constants of 5 nm. Here we have shown for the first time (a) a functional mimetic of a protein sequence, which activates a nuclear import receptor and (b) a mimetic of a protein sequence with a dual functionality. Tat11 is a lead compound which can potentially inhibit the HIV-1 life cycle by a dual mechanism: inhibition of nuclear import and of RNA binding.
影响因子：
10.5
作者：
CALNAN, BJ;BIANCALANA, S;FRANKEL, AD
通讯作者：
FRANKEL, AD
DOI：
10.1073/pnas.87.5.1744
发表时间：
1990-03-01
影响因子：
11.1
作者：
HEYDUK, T;LEE, JC
通讯作者：
LEE, JC
DOI：
10.1073/pnas.82.15.5131
发表时间：
1985-01-01
影响因子：
11.1
作者：
HOUGHTEN, RA
通讯作者：
HOUGHTEN, RA