A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus
A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus
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一种螺旋短肽融合抑制剂，对人类免疫缺陷病毒 1 型 (HIV-1)、HIV-2 和猿猴免疫缺陷病毒具有高效活性
DOI：
10.1128/jvi.01839-16
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发表时间：
2017-01-01
影响因子：
5.4
通讯作者：
He, Yuxian
中科院分区：
文献类型：
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作者：
Xiong, Shengwen;Borrego, Pedro;He, Yuxian
摘要人类免疫缺陷病毒2型(HIV-2)已经蔓延到全球不同地区，目前约有100万至200万人感染，这就需要对HIV-1和HIV-2分离株都有效的新的抗病毒药物。T20(Enfuvitide)是一种来源于gp41 C端七肽重复序列(ChR)的36肽，是临床上唯一被批准的HIV-1融合抑制剂，但它容易诱导耐药性，对HIV-2没有活性。在这项研究中，我们首先证明了M-T挂钩结构对于提高各种基于CHR的多肽抑制剂的结合稳定性和抑制活性也是至关重要的。然后，我们通过引入M-T挂钩结构、HIV-2序列和盐桥形成残基设计了一种新的短肽(23-聚体)，命名为2P23。有希望的是，2P23是一种高度稳定的螺旋多肽，与来自HIV-1、HIV-2和猴免疫缺陷病毒(SIV)的替代靶点具有高结合力。与此一致的是，2P23对不同亚型的HIV-1分离株、耐T20的HIV-1突变体以及一组HIV-2原代分离株、HIV-2突变体和SIV分离株具有很强的抑制活性。因此，我们认为2P23具有很高的临床应用潜力，也是探讨HIV-1/2和SIV介导的膜融合机制的理想工具。重要性：多肽药物T20是唯一被批准的艾滋病毒-1融合抑制剂，但它对艾滋病毒-2分离株不起作用，目前已感染100万至200万人，并继续在全球传播。最近的研究表明，M-T挂钩结构可以极大地增强gp41CHR衍生抑制剂的结合和抗病毒活性，特别是对原本没有活性的短肽。通过结合钩子结构、HIV-2序列和基于盐桥的策略，成功地设计了短肽2P23。2P23与许多其他多肽融合抑制剂相比显示出显著的优势，包括它对HIV-1、HIV-2甚至SIV分离株的有效和广泛的活性，它作为螺旋寡聚肽的稳定性，以及它与不同靶点的高结合。2P23的小尺寸有利于其合成，并可显著降低生产成本。因此，2P23是进一步发展的理想候选基因，也为研究HIV-1/2和SIV介导的细胞融合提供了一种新的工具。
ABSTRACT Human immunodeficiency virus type 2 (HIV-2) has already spread to different regions worldwide, and currently about 1 to 2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T20 (enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug resistance and is not active on HIV-2. In this study, we first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1/2- and SIV-mediated membrane fusion. IMPORTANCE The peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors, including its potent and broad activity on HIV-1, HIV-2, and even SIV isolates, its stability as a helical, oligomeric peptide, and its high binding to diverse targets. The small size of 2P23 would benefit its synthesis and significantly reduce production cost. Therefore, 2P23 is an ideal candidate for further development, and it also provides a novel tool for studying HIV-1/2- and SIV-mediated cell fusion.