Therapeutics to Prevent/Treat Lassa Fever Virus

项目总监/首席调查员(最后、第一、中间)：Oldstone，Michael-2 R01 AI055540-06 修订摘要部分 由阿雷纳病毒拉萨病毒(LASV)、马丘波病毒(MACV)、瓜纳里托病毒(GTOV)和朱宁病毒(JUNV)引起的病毒性出血热(VHF)是一种毁灭性的人类疾病，病死率为15%至35%。目前可用的抗病毒治疗有限。通过高通量筛选合成的组合小分子文库和带有这些高致病性ArenaVirus糖蛋白(GP)的伪型病毒粒子，我们鉴定了病毒抑制剂。我们的候选小分子抑制剂对旧世界和新世界出血性禽流感病毒都有很高的活性。初步研究表明，当在疾控中心的BSL-4中进行测试时，它们有效地阻止了ArenaVirus GPs(IC50为200-350 NM)依赖于pH的融合，并阻止了这些人类致病病毒在培养细胞中的感染。 我们目前的提案计划通过二次文库合成和筛选的迭代来优化最有效的先导化合物。优化的化合物将在细胞培养中测试它们的抗病毒潜力，并在新开发的小动物模型中评估它们对LASV的抑制潜力。我们将调查我们主要候选者的详细作用机制，并解决抗药性病毒变体的开发问题。我们期待着对治疗这些BSL-4药物的药物开发做出重大贡献。

Program Director/Principal Investigator (Last, First, Middle): Oldstone, Michael - 2 R01 AI055540-06 REVISED ABSTRACT SECTION Viral hemorrhagic fevers (VHF) caused by the arenaviruses Lassa virus (LASV), Machupo (MACV), Guanarito (GTOV), and Junin virus (JUNV) are devastating human diseases with fatality rates of 15 to 35%. There is limited antiviral treatment available. Using high-throughput screening of synthetic combinatorial small molecule libraries coupled with pseudotyped virion particles bearing the glycoproteins (GPs) of these highly pathogenic arenaviruses, we identified viral inhibitors. Our candidate small molecule inhibitors are highly active against both Old World and New World hemorrhagic arenaviruses. Initial studies revealed they efficiently block pH-dependent fusion by the arenavirus GPs (IC50 of 200-350 nM) and blocked infection by these human pathogenic viruses in cultured cells when tested in BSL-4 at the CDC. Our current proposal plans to optimize the most potent lead compounds by iterations of secondary library synthesis and screening. Optimized compounds will be tested for their anti-viral potential in cell culture and inhibitory potential against LASV assessed in a newly developed small animal model. The detailed mechanism of action of our lead candidates will be investigated and the development of drug resistant viral variants addressed. We anticipate making a significant contribution to drug development to treat these BSL-4 agents.