Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90025, USA.
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3157-62. doi: 10.1073/pnas.0909587107. Epub 2010 Jan 28.
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.
我们描述了一种抗病毒小分子化合物 LJ001，它能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、副粘病毒、黄病毒和 HIV-1。相比之下，该化合物对非包膜病毒的感染没有影响。体外和体内实验均未显示出明显的毒性。LJ001 特异性地插入病毒膜中，不可逆地使病毒失活，同时保留功能完整的包膜蛋白，并在病毒结合后但在病毒-细胞融合之前抑制病毒进入。LJ001 预处理还可预防埃博拉病毒和裂谷热病毒引起的死亡率。作为一种类萝藦素衍生物，LJ001 的构效关系分析表明，LJ001 的极性和非极性末端都与其抗病毒活性有关。LJ001 特异性地抑制病毒-细胞但不抑制细胞-细胞融合，进一步的脂质生物合成抑制剂研究表明，LJ001 利用了静态病毒膜和具有修复能力的生物合成细胞膜之间的治疗窗。总之，我们的数据揭示了一类针对包膜病毒的广谱抗病毒药物，这些药物靶向病毒脂质膜，并损害其介导病毒-细胞融合的能力。
