预防/治疗拉沙热病毒的疗法-猫眼课题宝

预防/治疗拉沙热病毒的疗法

批准号：

7842621

负责人：

MICHAEL B OLDSTONE

金额：

$47.48万

依托单位：

SCRIPPS RESEARCH INSTITUTE, THE

依托单位国家：

美国

项目类别：

财政年份：

2004

资助国家：

美国

项目状态：

已结题

起止时间：

2004-05-01 至 2011-04-30

来源：

https://reporter.nih.gov/project-details/7842621

关键词：

Address Affinity Affinity Chromatography Africa Air Amino Acids Animal Model Antiviral Agents Area Arenavirus Arenavirus Infections Binding Biochemical Biological Availability Categories Cell Culture Techniques Cells Cellular Tropism Centers for Disease Control and Prevention (U.S.)Characteristics Chemical Structure Clinical Collaborations Complex Confocal Microscopy Coupled Cultured Cells Cytoplasmic Tail Development Disease Drug Delivery Systems Drug effect disorder Drug resistance Epithelial Cells Escape Mutant Evaluation Evolution Exhibits Extracellular Matrix Proteins Family Fibroblasts Frequencies Generations Genetic Genetic Transcription Glycopeptides Glycoproteins Grant Guanarito virus Hepatocyte Human Immune Immune response Immune system Immunobiology In Vitro Individual Infection Inhibitory Concentration 50 Investigation Iowa Junin virus Label Lassa fever virus Lassa virus Lead Libraries Licensing Life Lymphocytic choriomeningitis virus Maps Mediating Membrane Membrane Fusion Modeling Molecular Mechanisms of Action Molecular Probes Morbidity - disease rate Mus Old World Arenaviruses Patients Peptide Signal Sequences Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Photoaffinity Labels Principal Investigator Probability Production Public Health RNA Viruses RNA replication Recombinants Resistance Retroviridae Ribavirin Role Screening procedure Series Site-Directed Mutagenesis South American hemorrhagic fever viruses Specificity Structure Structure-Activity Relationship Techniques Testing Therapeutic Therapeutic Index Therapeutic Intervention Threonine Time Toxic effect Universities Vaccines Validation Variant Vascular Endothelial Cell Vertebral column Viral Viral Hemorrhagic Fevers Viral Pathogenesis Viral Physiology Virion Virus Virus Diseases Virus Inhibitors Virus Receptors abstracting analog base cell killing cell type combinatorial drug candidate drug development drug resistant virus high throughput screening human disease in vivo inhibitor/antagonist man metropolitan mortality novel nucleoside analog particle pathogen polypeptide positional cloning prevent programs prophylactic receptor small molecule small molecule libraries trafficking viral RNA

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中文摘要

翻译

项目负责人/主要研究者（最后一名、第一名、中间名）：Oldstone，Michael - 2 R 01 AI 055540 -06 修订摘要部分由沙粒病毒拉沙病毒（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）是具有15 - 35%致死率的毁灭性人类疾病。抗病毒治疗有限。使用高通量筛选的合成组合的小分子文库加上假型病毒粒子轴承这些高致病性沙粒病毒的糖蛋白（GP），我们确定了病毒抑制剂。我们的候选小分子抑制剂对旧世界和新世界出血性沙粒病毒都具有高度活性。初步研究表明，它们有效地阻断沙粒病毒GP的pH依赖性融合（IC 50为200-350 nM），并在CDC的BSL-4中测试时阻断这些人类病原性病毒在培养细胞中的感染。我们目前的建议计划通过二级库合成和筛选的迭代来优化最有效的先导化合物。将测试优化的化合物在细胞培养中的抗病毒潜力，并在新开发的小动物模型中评估对LASV的抑制潜力。我们将研究我们的主要候选药物的详细作用机制，并解决耐药病毒变体的发展。我们期望为治疗这些BSL-4药物的药物开发做出重大贡献。

英文摘要

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.

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