A broad-spectrum antiviral targeting entry of enveloped viruses
A broad-spectrum antiviral targeting entry of enveloped viruses
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DOI：
10.1073/pnas.0909587107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Lee, Benhur
中科院分区：
文献类型：
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作者：
Wolf, Mike C.;Freiberg, Alexander N.;Lee, Benhur
我们描述了一种抗病毒小分子 LJ001，可有效对抗多种包膜病毒，包括甲型流感病毒、丝状病毒、痘病毒、沙粒病毒、布尼亚病毒、副粘病毒、黄病毒和 HIV-1。与此形成鲜明对比的是，该化合物对无包膜病毒的感染没有影响。体外和体内试验显示没有明显的毒性。 LJ001特异性嵌入病毒膜中，不可逆地灭活病毒颗粒，同时保留功能完整的包膜蛋白，并在病毒结合后、病毒与细胞融合之前的步骤抑制病毒进入。 LJ001 预处理还可以预防埃博拉病毒和裂谷热病毒引起的死亡。 LJ001（一种绕丹宁衍生物）的结构-活性关系分析表明，LJ001 的极性和非极性末端均与其抗病毒活性有关。 LJ001 特异性抑制病毒-细胞，但不抑制细胞-细胞融合，对脂质生物合成抑制剂的进一步研究表明，LJ001 利用了静态病毒膜和具有修复能力的生物细胞膜之间存在的治疗窗口。总之，我们的数据揭示了一类广谱抗病毒药物，可有效对抗有包膜病毒，这些病毒靶向病毒脂质膜并损害其介导病毒-细胞融合的能力。
We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus-cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure-activity relationship analyses of LJ001, a rhodanine derivative, implicated both the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus-cell but not cell-cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus-cell fusion.