Viral Entry Inhibitors Targeted to the Membrane Site of Action
Viral Entry Inhibitors Targeted to the Membrane Site of Action
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DOI：
10.1128/jvi.00135-10
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发表时间：
2010-07-01
影响因子：
5.4
通讯作者：
Moscona, Anne
中科院分区：
文献类型：
--
作者：
Porotto, Matteo;Yokoyama, Christine C.;Moscona, Anne
被包裹的病毒与宿主细胞的融合是由专门的融合蛋白驱动的，以启动感染。“Class I”融合蛋白含有两个区域，通常是两个七肽重复(HR)结构域，这两个区域是导致融合的复杂构象变化的中心：第一个七肽重复(HRN)与融合肽相邻，第二个(HRC)紧邻跨膜区。来自HR区域的多肽可以抑制融合，其中一种HR多肽T20(Enfuviride)正在临床上用于HIV-1。对于副粘病毒，两种膜蛋白的活性，即受体结合蛋白(血凝素神经氨酸酶[HN]或G)和融合蛋白(F)，启动病毒进入。HN或G与靶细胞上其受体的结合触发了F的激活，然后F插入到靶细胞中，并介导了启动感染的膜融合。我们已经证明，对于副粘病毒，HR多肽的抑制效果与F激活速率成反比。对于HIV-1，通过添加胆固醇基团，将HRC衍生的多肽靶向发生融合的膜微域，可以显著提高其抗病毒效力。我们在这里报告了三种副粘病毒-人类副流感病毒3型(HPIV3)，婴儿下呼吸道疾病的主要原因，以及新出现的人畜共患病毒亨德拉病毒(HEV)和尼帕病毒(NIV)，它们会导致致命的中枢神经系统疾病-在副粘病毒HRC衍生的多肽中添加胆固醇使抗病毒效力增加2个对数单位。我们的数据表明，这种增强的活性确实是多肽靶向发生融合的质膜的结果。细胞表面的胆固醇标记的多肽创建了一个保护性的抗病毒屏障，直接针对其作用部位的F蛋白，并扩大了抑制多肽对副粘病毒的潜在用途。
The fusion of enveloped viruses with the host cell is driven by specialized fusion proteins to initiate infection. The "class I" fusion proteins harbor two regions, typically two heptad repeat (HR) domains, which are central to the complex conformational changes leading to fusion: the first heptad repeat (HRN) is adjacent to the fusion peptide, while the second (HRC) immediately precedes the transmembrane domain. Peptides derived from the HR regions can inhibit fusion, and one HR peptide, T20 (enfuvirtide), is in clinical use for HIV-1. For paramyxoviruses, the activities of two membrane proteins, the receptor-binding protein (hemagglutinin-neuraminidase [HN] or G) and the fusion protein (F), initiate viral entry. The binding of HN or G to its receptor on a target cell triggers the activation of F, which then inserts into the target cell and mediates the membrane fusion that initiates infection. We have shown that for paramyxoviruses, the inhibitory efficacy of HR peptides is inversely proportional to the rate of F activation. For HIV-1, the antiviral potency of an HRC-derived peptide can be dramatically increased by targeting it to the membrane microdomains where fusion occurs, via the addition of a cholesterol group. We report here that for three paramyxoviruses-human parainfluenza virus type 3 (HPIV3), a major cause of lower respiratory tract diseases in infants, and the emerging zoonotic viruses Hendra virus (HeV) and Nipah virus (NiV), which cause lethal central nervous system diseases-the addition of cholesterol to a paramyxovirus HRC-derived peptide increased antiviral potency by 2 log units. Our data suggest that this enhanced activity is indeed the result of the targeting of the peptide to the plasma membrane, where fusion occurs. The cholesterol-tagged peptides on the cell surface create a protective antiviral shield, target the F protein directly at its site of action, and expand the potential utility of inhibitory peptides for paramyxoviruses.