A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41
A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41
复制标题
一种新型双特异性肽 HIV-1 融合抑制剂，靶向 gp41 中的 N 端七肽重复序列和融合肽结构域
DOI：
10.1007/s00726-016-2325-x
复制
发表时间：
2016-12-01
期刊：
影响因子：
3.5
通讯作者：
Liu, Keliang
中科院分区：
文献类型：
--
作者：
Jiang, Xifeng;Jia, Qiyan;Liu, Keliang
HIV - 1与靶细胞的融合是由gp41融合肽（FP）插入靶细胞膜以及gp41的N端和C端七肽重复序列（NHR和CHR）之间的相互作用引发的，随后形成六螺旋束（6 - HB）融合核心。因此，FP和NHR都是HIV - 1融合抑制剂的重要靶点。在此，我们设计并合成了一种双靶点肽类HIV - 1融合抑制剂，4HR - LBD - VIRIP，其中4HR - LBD能够与gp41的NHR结构域结合，而VIRIP能够与gp41的FP相互作用。我们发现4HR - LBD - VIRIP在抑制HIV - 1（IIIB）感染和HIV - 1包膜糖蛋白（Env）介导的细胞 - 细胞融合方面比4HR - LBD和VIRIP的效力高约十倍，这表明这种双靶点HIV - 1融合抑制剂具有很强的协同抗病毒作用。一项生物物理分析表明，4HR - LBD - VIRIP能够与包含gp41的NHR和FP结构域的N70肽相互作用，并与脂质膜结合。这项研究为设计针对HIV和其他具有I类膜融合蛋白的包膜病毒的新型病毒融合抑制剂提供了一种新方法。
HIV-1 fusion with the target cell is initiated by the insertion of the gp41 fusion peptide (FP) into the target cell membrane and the interaction between the gp41 N- and C-terminal heptad repeats (NHR and CHR), followed by the formation of the six-helix bundle (6-HB) fusion core. Therefore, both FP and NHR are important targets for HIV-1 fusion inhibitors. Here, we designed and synthesized a dual-target peptidic HIV-1 fusion inhibitor, 4HR-LBD-VIRIP, in which 4HR-LBD is able to bind to the gp41 NHR domain, while VIRIP is able to interact with gp41 FP. We found that 4HR-LBD-VIRIP is about tenfold more potent than 4HR-LBD and VIRIP in inhibiting HIV-1IIIBinfection and HIV-1 envelope glycoprotein (Env)-mediated cell–cell fusion, suggesting that this dual-target HIV-1 fusion inhibitor possesses a strong synergistic antiviral effect. A biophysical analysis indicates that 4HR-LBD-VIRIP can interact with N70 peptide that contains the gp41 NHR and FP domains and binds with lipid membrane. This study provides a new approach for designing novel viral fusion inhibitors against HIV and other enveloped viruses with class I membrane fusion proteins.