Rationally Designed Anti-HIV Peptides Containing Multifunctional Domains as Molecule Probes for Studying the Mechanisms of Action of the First and Second Generation HIV Fusion Inhibitors
Rationally Designed Anti-HIV Peptides Containing Multifunctional Domains as Molecule Probes for Studying the Mechanisms of Action of the First and Second Generation HIV Fusion Inhibitors
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DOI：
10.1074/jbc.m804672200
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发表时间：
2008-10-31
影响因子：
4.8
通讯作者：
Jiang, Shibo
中科院分区：
文献类型：
--
作者：
Qi, Zhi;Shi, Weiguo;Jiang, Shibo
我们先前已经表明，第一代人免疫缺陷病毒（HIV）融合抑制剂T20（Fuzeon）含有关键的脂质结合结构域（LBD），而C34（衍生自gp 41 C-末端七肽重复的另一种抗HIV肽）由重要的口袋结合结构域（PBD）组成，并且两者共享共同的4-3个七肽重复（HR）序列（Liu，S.，王静，Cheung，B.，吕，H.，孙，J.，Yan，X.，牛，J.，Farmar，J.，吴，S.，和Jiang，S.（2007）J.Biol.Chem.282，9612-9620）。T1249是第二代HIV融合抑制剂，具有LBD和PBD，但HR序列不同，表明这三种抗HIV肽可能具有不同的作用机制。在这里，我们合理地设计了一组肽，其中包含多个拷贝的预测HR序列（5 HR）或HR序列加上LBD（4 HR-LBD）或PBD（PBD-4 HR）或两者（PBD-3 HR-LBD），我们比较了它们的抗HIV-1活性和生物物理特性。我们发现肽5 HR对HIV-1介导的细胞-细胞融合表现出低至中等的抑制活性，而在HR序列中加入LBD和/或PBD导致抗HIV-1活性的显著增加。含PBD的多肽（PBD-4 HR和PBD-3 HR-LBD）能与N肽N46形成稳定的六螺旋束，有效地阻断gp 41核心的形成; G. 4 HR-LBD和PBD-3 HR-LBD可与脂质载体相互作用。这些结果表明，在这些抗HIV肽的HR序列作为一个结构域，并负责其与HR序列的相互作用的N-末端七肽重复，而PBD和LBD是关键的相互作用，其相应的目标。T20、C34和T1249的功能可能分别类似于4 HR-LBD、PBD-4 HR和PBD-3 HR-LBD，与不同的靶位点相互作用以抑制HIV融合和进入。因此，本研究为了解消化性HIV-1融合抑制剂的作用机制，合理设计抗HIV和其他I类融合病毒的新型抗病毒多肽提供了重要信息。
We have previously shown that the first generation human immunodeficiency virus (HIV) fusion inhibitor T20 (Fuzeon) contains a critical lipid-binding domain (LBD), whereas C34, another anti-HIV peptide derived from the gp41 C-terminal heptad repeat, consists of an important pocket-binding domain (PBD), and both share a common 4-3 heptad repeat (HR) sequence (Liu, S., Jing, W., Cheung, B., Lu, H., Sun, J., Yan, X., Niu, J., Farmar, J., Wu, S., and Jiang, S. (2007) J. Biol. Chem. 282, 9612-9620). T1249, the second generation HIV fusion inhibitor, has both LBD and PBD but a different HR sequence, suggesting that these three anti-HIV peptides may have distinct mechanisms of action. Here we rationally designed a set of peptides that contain multiple copies of a predicted HR sequence (5HR) or the HR sequence plus either LBD (4HR-LBD) or PBD (PBD-4HR) or both (PBD-3HR-LBD), and we compared their anti-HIV-1 activity and biophysical properties. We found that the peptide 5HR exhibited low-to-moderate inhibitory activity on HIV-1-mediated cell-cell fusion, whereas addition of LBD and/or PBD to the HR sequence resulted in a significant increase of the anti-HIV-1 activity. The peptides containing PBD, including PBD-4HR and PBD-3HR-LBD, could form a stable six-helix bundle with the N-peptide N46 and effectively blocked the gp41 core formation, whereas the peptides containing LBD, e. g. 4HR-LBD and PBD-3HR-LBD, could interact with the lipid vehicles. These results suggest that the HR sequence in these anti-HIV peptides acts as a structure domain and is responsible for its interaction with the HR sequence in N-terminal heptad repeat, whereas PBD and LBD are critical for interactions with their corresponding targets. T20, C34, and T1249 may function like 4HR-LBD, PBD-4HR, and PBD-3HR-LBD, respectively, to interact with different target sites for inhibiting HIV fusion and entry. Therefore, this study provides important information for understanding the mechanisms of action of the peptic HIV-1 fusion inhibitors and for rational design of novel antiviral peptides against HIV and other viruses with class I fusion proteins.