Anti-tick-borne Encephalitis Virus Miniprotein Agents

抗蜱传脑炎病毒微蛋白制剂

• 批准号: 6932275
• 负责人: Robert O. Fox
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932275
• 关键词: Flaviviridae; Tick borne encephalitis virus; West Nile virus; X ray crystallography; antiviral agents; bioterrorism /chemical warfare; cell surface receptors; combinatorial chemistry; conformation; electron microscopy; encephalitis virus; host organism interaction; laboratory mouse; nuclear magnetic resonance spectroscopy; peptide chemical synthesis; phage display; protein binding; protein protein interaction; protein structure function; recombinant proteins; tissue /cell culture; virus envelope; virus protein

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（由申请人提供）：我们之前的研究已经提供了一个原理证明，可以开发一种富含二硫化物的小蛋白，它可以阻断Langat （LGT）病毒对细胞的感染，Langat （LGT）病毒是一种自然减毒的病毒，是黄病毒属蜱传脑炎（TBE）血清群致病性成员的模型。通过筛选构象受限的组合微小蛋白噬菌体展示文库，选择第一代微小蛋白MP-100与LGT病毒包膜(E)蛋白纯化的重组结构域III （D3）结合。微小蛋白MP-100可阻断蜱传LGT和波瓦桑病毒对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有抗病毒作用。在此期间，我们的目标是开发第二代结合更紧密的微型蛋白，与目前的MP-100序列相比，具有更好的抗TBE血清组黄病毒的抗病毒活性。我们的目标是开发一种抗病毒的微小蛋白，它可以有效地对抗广泛的TBE血清组中潜在的黄病毒生物恐怖威胁因子，包括中欧蜱传脑炎（株Kumlinge）、Kyasanur森林病（FD）、鄂木斯克出血热（OHF）和俄罗斯春夏脑炎（RSSE）病毒。我们将确定优化的MP-100与OHF-E-D3和相关的TBE血清组e - d3的紧密结合类似物，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。抗脑炎病毒微型蛋白的开发将成为开发针对其他黄病毒的微型蛋白的模型，这些黄病毒也是潜在的生物恐怖主义威胁剂或新出现的疾病，包括登革热、日本脑炎和西尼罗河。