Lee Andrew M, Rojek Jillian M, Spiropoulou Christina F, Gundersen Anette T, Jin Wei, Shaginian Alex, York Joanne, Nunberg Jack H, Boger Dale L, Oldstone Michael B A, Kunz Stefan
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
J Biol Chem. 2008 Jul 4;283(27):18734-42. doi: 10.1074/jbc.M802089200. Epub 2008 May 12.
Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and Machupo, Guanarito, Junin, and Sabia virus in South America are among the most devastating emerging human diseases with fatality rates of 15-35% and a limited antiviral therapeutic repertoire available. Here we used high throughput screening of synthetic combinatorial small molecule libraries to identify inhibitors of arenavirus infection using pseudotyped virion particles bearing the glycoproteins (GPs) of highly pathogenic arenaviruses. Our screening efforts resulted in the discovery of a series of novel small molecule inhibitors of viral entry that are highly active against both Old World and New World hemorrhagic arenaviruses. We observed potent inhibition of infection of human and primate cells with live hemorrhagic arenaviruses (IC(50)=500-800 nm). Investigations of the mechanism of action revealed that the candidate compounds efficiently block pH-dependent fusion by the arenavirus GPs (IC(50) of 200-350 nm). Although our lead compounds were potent against phylogenetically distant arenaviruses, they did not show activity against other enveloped viruses with class I viral fusion proteins, indicating specificity for arenavirus GP-mediated membrane fusion.
由非洲的拉沙病毒以及南美洲的马丘波病毒、瓜纳里托病毒、胡宁病毒和赛比亚病毒等沙粒病毒引起的病毒性出血热，是最具毁灭性的新发人类疾病之一，其致死率为15%至35%，且可用的抗病毒治疗方法有限。在此，我们利用对合成组合小分子文库进行高通量筛选，以带有高致病性沙粒病毒糖蛋白（GPs）的假型病毒粒子来鉴定沙粒病毒感染的抑制剂。我们的筛选工作发现了一系列新型的病毒进入小分子抑制剂，它们对旧大陆和新大陆出血性沙粒病毒均具有高活性。我们观察到它们能有效抑制人类和灵长类细胞被活出血性沙粒病毒感染（IC(50)=500 - 800纳米）。对作用机制的研究表明，候选化合物能有效阻断沙粒病毒GPs介导的pH依赖性融合（IC(50)为200 - 350纳米）。尽管我们的先导化合物对系统发育上距离较远的沙粒病毒具有强效作用，但它们对其他具有I类病毒融合蛋白的包膜病毒没有活性，这表明其对沙粒病毒GP介导的膜融合具有特异性。
