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Anti-tick-borne Encephalitis Virus Miniprotein Agents

抗蜱传脑炎病毒微蛋白制剂

基本信息

批准号：
7348316
负责人：
Robert O. Fox
金额：
$ 35.11万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7348316
关键词：
Acids Affinity American Animal Model Animal Testing Animals Antiviral Agents Attenuated Behavior Binding Biological Biological Assay Biological Models Cell Surface Receptors Cells Cellular biology Chemicals Class Collaborations Complex Condition Coupled Cultured Cells Cytoplasm Data Dengue Development Disease Disulfides Drug Design E protein Encephalitis Encephalitis Viruses Endocytosis European Tick-Borne Encephalitis Flavivirus Generations Genomics Goals Health Infection Japanese Encephalitis Kyasanur Forest Disease Laboratories Langat virus Libraries Maps Modeling Molecular Biology Molecular Conformation Monkeys Mus NMR Spectroscopy New Agents Omsk Hemorrhagic Fever Omsk hemorrhagic fever virus Pan Genus Phage Display Pharmaceutical Preparations Placement Positioning Attribute Powassan virus Proteins RNA Range Receptor Cell Recombinants Refractory Research Risk Route Russian Spring-Summer Encephalitis Sampling Site Software Design Solutions Structure Techniques Test Result Testing Thinking Tick-Borne Encephalitis Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Ticks United States Vaccines Variant Vesicle Viral Viral Hemorrhagic Fevers Virus Virus Receptors West Nile virus Yellow Fever analog base biosafety level 4 facility combinatorial conotoxin GI design env Gene Products improved innovation interest kidney cell member mimetics model development monomer novel prevent protein E protein aminoacid sequence scaffold small molecule success tissue/cell culture virology virus envelope

项目摘要

DESCRIPTION (provided by applicant): Our previous studies have provided a proof-of-principle that a small disulfide-rich miniprotein can be developed that will block the infection of cells by Langat (LGT) virus, a naturally attenuated virus that is a model for the pathogenic members of the tick-borne encephalitis (TBE) serogroup of the Flavivirus genus. A first generation miniprotein, termed MP-100, was selected by panning a conformationally restrained combinatorial miniprotein phage display library for binding with purified recombinant domain III (D3) of the LGT virus envelope (E) protein. The miniprotein MP-100 was shown to block infection of Vero and LLC-MK2 monkey kidney cell cultures by tick-borne LGT and Powassan viruses. Further studies indicated an antiviral effect in a mouse animal model. Our objective during this period of support is the development of a second-generation, more tightly binding miniprotein with improved antiviral activity against TBE serogroup flaviviruses compared to the current MP-100 sequence. Our goal is to develop an antiviral miniprotein that is effective against a broad range of potential flavivirus bioterrorist threat agents in the TBE serogroup, including Central European tick-borne encephalitis (strain Kumlinge), Kyasanur Forest Disease (FD), Omsk Hemorrhagic Fever (OHF) and Russian Spring Summer encephalitis (RSSE) viruses. We will identify optimized tight-binding analogs of MP-100 to OHF-E-D3 and the related TBE serogroup E-D3s, and determine if they have enhanced antiviral activity in tissue culture cells and in animals. The development of anti-TBE virus miniproteins will serve as a model for the development of miniproteins against other flaviviruses that are also potential bioterrorist threat agents or emerging diseases, including dengue, Japanese encephalitis and West Nile.

描述（由申请方提供）：我们之前的研究提供了一个原理证明，即可以开发一种富含二硫化物的小微蛋白，其将阻断Langat（LGT）病毒对细胞的感染，Langat（LGT）病毒是一种天然减毒病毒，是黄病毒属蜱传脑炎（TBE）血清群致病成员的模型。通过淘选构象受限的组合微蛋白噬菌体展示文库以与LGT病毒包膜（E）蛋白的纯化重组结构域III（D3）结合来选择第一代微蛋白，称为MP-100。微蛋白MP-100可阻断蜱传LGT和Powassan病毒对Vero和LLC-MK2猴肾细胞培养物的感染。进一步的研究表明在小鼠动物模型中具有抗病毒作用。在此支持期间，我们的目标是开发第二代，与目前的MP-100序列相比，对TBE血清群黄病毒具有更高抗病毒活性的更紧密结合的微蛋白。我们的目标是开发一种抗病毒微蛋白，可有效对抗TBE血清群中广泛的潜在黄病毒生物恐怖威胁因子，包括中欧蜱传脑炎（Kumlinge株），Kyasanur森林病（FD），鄂木斯克出血热（OHF）和俄罗斯春夏脑炎（RSSE）病毒。我们将鉴定MP-100与OHF-E-D3和相关TBE血清群E-D3的优化紧密结合类似物，并确定它们是否在组织培养细胞和动物中具有增强的抗病毒活性。抗TBE病毒微蛋白的开发将作为开发针对其他黄病毒的微蛋白的模型，这些黄病毒也是潜在的生物恐怖主义威胁因子或新出现的疾病，包括登革热、日本脑炎和西尼罗河病毒。