Inhibition of Nipah virus infection in vivo: targeting an early stage of paramyxovirus fusion activation during viral entry.
Inhibition of Nipah virus infection in vivo: targeting an early stage of paramyxovirus fusion activation during viral entry.
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DOI：
10.1371/journal.ppat.1001168
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发表时间：
2010-10-28
期刊：
影响因子：
6.7
通讯作者：
Moscona A
中科院分区：
文献类型：
--
作者：
Porotto M;Rockx B;Yokoyama CC;Talekar A;Devito I;Palermo LM;Liu J;Cortese R;Lu M;Feldmann H;Pessi A;Moscona A
在副粘病毒细胞进入过程中，受体结合触发融合蛋白（F）的构象变化，导致病毒和细胞膜融合。来自F中C-末端七肽重复（HRC）区域的肽已显示通过阻止促融合六螺旋束的形成来抑制融合。我们最近表明，在HRC肽中加入胆固醇基团对尼帕病毒有活性，将这些肽靶向融合发生的膜，大大增加了它们的抗病毒作用。在这项工作中，我们报告说，不像未标记的HRC肽，它结合到假定的扩展中间状态桥接病毒和细胞膜，胆固醇标记的HRC衍生肽与F相互作用的融合肽插入到靶细胞膜之前，从而捕获在F-激活过程的早期阶段。此外，我们表明，胆固醇标记使这些肽在体内具有活性：胆固醇标记的肽穿过血脑屏障，并有效地预防和治疗建立的动物模型，否则将是致命的尼帕病毒脑炎。胆固醇标记的肽的体内功效，特别是它们穿透CNS的能力，表明它们是预防或治疗尼帕病毒和其他致命副粘病毒感染的有希望的候选物。尼帕病毒（Nipah，NiV）和亨德拉病毒（Hendra，HeV）是两种新出现的人畜共患副粘病毒。除了急性感染外，这些病毒还可能导致迟发性疾病或最初感染数年后脑炎复发，以及持续或延迟的神经系统后遗症。我们提出了一种新的策略来预防和治疗NiV/HeV感染，可能广泛适用于包膜病毒病原体。包膜病毒必须将它们的膜与靶细胞膜融合以启动感染，并且阻断这一步骤可以预防或治疗感染，如临床上验证的HIV。然而，对于副粘病毒，结合病毒融合蛋白的肽已显示在体外抑制融合，但在体内不抑制融合。我们在这里提出的新策略为临床有效的副粘病毒融合抑制肽打开了大门。通过使用胆固醇标签将融合抑制肽靶向靶膜，我们捕获了病毒融合激活过程的早期阶段，从而大大增强了这些肽抑制病毒进入的功效。重要的是，这种策略可以预防和治疗体内致命的尼帕病毒感染。因此，抗病毒肽的膜靶向为开发针对重要人类病原体的高效肽融合抗病毒药物提供了新的途径。
In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses. Nipah (NiV) and Hendra (HeV) viruses are two lethal emerging zoonotic paramyxoviruses. In addition to acute infection, these viruses may lead to late-onset disease or relapse of encephalitis years after initial infection, as well as persistent or delayed neurological sequelae. We present a new strategy to prevent and treat NiV/HeV infection that may be broadly applicable for enveloped viral pathogens. Enveloped viruses must fuse their membrane with the target cell membrane in order to initiate infection, and blocking this step can prevent or treat infection, as clinically validated for HIV. For paramyxoviruses, however, peptides that bind the viral fusion protein have been shown to inhibit fusion in vitro, but not in vivo. The new strategy that we present here opens the door to clinically effective paramyxovirus fusion-inhibitory peptides. By targeting fusion-inhibitory peptides to the target membrane using a cholesterol tag, we capture an early stage in the viral fusion-activation process, thus drastically enhancing the efficacy of these peptides at inhibiting viral entry. Importantly, this strategy prevents and treats lethal Nipah virus infection in vivo. Membrane targeting of antiviral peptides thus offers a new approach to development of highly effective peptide fusion antivirals against important human pathogens.
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