A novel HIV-1 gp41 tripartite model for rational design of HIV-1 fusion inhibitors with improved antiviral activity
A novel HIV-1 gp41 tripartite model for rational design of HIV-1 fusion inhibitors with improved antiviral activity
复制标题
一种新型HIV-1 gp41三方模型，用于合理设计具有改进抗病毒活性的HIV-1融合抑制剂
DOI：
10.1097/qad.0000000000001415
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发表时间：
2017-04-24
期刊：
影响因子：
3.8
通讯作者：
Lu, Lu
中科院分区：
文献类型：
--
作者：
Su, Shan;Wang, Qian;Lu, Lu
目的：在HIV-1融合过程中，HIV-1糖蛋白41(Gp41)的N端七肽重复序列(NHR)与C端七肽重复序列(CHR)相互作用形成具有融合活性的六螺旋束，是设计基于CHR多肽的HIV-1融合抑制剂的有效靶点。为了克服简化的六螺旋束螺旋轮模型的局限性，我们开发了一种新的HIV-1 gp41 NHRCHR-NHR三方模型，用于合理设计具有更高抗病毒活性的HIV-1融合抑制剂。设计：基于六螺旋束的晶体结构，我们评估了CHR中每个残基的NHR结合特性。在这个新的三方模型中，ChR残基分为主结合部位、非结合部位和辅助结合部位三类。方法：设计合成8个ChR多肽，以验证三方模型的有效性。结果：在这个三方模型中，辅助结合位点上的替换可增强或减弱对HIV-1感染的抑制作用。在我们的三方模型中，我们发现了三个具有ChR辅助结合位点残基突变的多肽，但在螺旋轮模型中没有结合位点。这些突变多肽的抗HIV-1活性是基于螺旋轮模型设计的C34的26倍。结论：这些数据验证了新的三方模型用于HIV-1融合抑制剂的合理设计的优越性和有效性。该方法可用于设计针对具有I类膜融合蛋白的包膜病毒的病毒融合抑制剂。版权所有(C)2017 Wolters KluwerHealth，Inc.保留所有权利。
Objectives: During HIV-1 fusion process, the N-terminal heptad repeat (NHR) of the HIV-1 glycoprotein 41 (gp41) interacts with the C-terminal heptad repeat (CHR) to form the fusion active six-helix bundle, thus being an effective target for the design of CHR peptide-based HIV-1 fusion inhibitors. To overcome the limitations of the simplified helix wheel model of six-helix bundle, we herein developed a novel HIV-1 gp41 NHRCHR- NHR tripartite model for the rational design of HIV-1 fusion inhibitors with improved antiviral activities.Design: Based on the crystal structure of six-helix bundle, we evaluated the NHRbinding properties of each residue in CHR. In this new tripartite model, CHR residues were divided into three groups: major binding, nonbinding, and assistant binding sites.Methods: Eight CHR peptides were designed and synthesized to confirm the validity of the tripartite model. Their affinities to NHR and inhibitory activities were analyzed.Results: In this tripartite model, replacements in assistant binding sites either increased or decreased the inhibition of HIV-1 infection. We identified three peptides with mutations of the residues in CHR at the assistant binding sites in our tripartite model but nonbinding sites in the helical wheel model. These mutant peptides had anti-HIV-1 activity up to 26-fold more potent than that of C34, a CHR peptide designed on the basis of the helix wheel model.Conclusion: These data verified the superiority and validity of our new tripartite model for the rational design of HIV-1 fusion inhibitors. This approach can be adapted for designing viral fusion inhibitors against other enveloped viruses with class I membrane fusion protein. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.