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）：我们以前的研究提供了原则上的证明，可以开发出一种富含二硫化的微型蛋白质，可以阻止Langat（LGT）病毒的细胞感染，Langat（LGT）病毒是一种自然减弱的病毒，是tick-barorne concephaliation（TBE）cyphaloge temogroup flavivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivirus te。通过平移构象约束的组合小蛋白噬菌体噬菌体显示库来选择一种称为MP-100的第一代微型蛋白，以与LGT病毒包膜（E）蛋白的纯化重组结构域III（D3）结合。小型蛋白MP-100被证明可通过tick传播LGT和Powassan病毒阻止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。我们在这一支持期间的目标是与当前的MP-100序列相比，针对血清群黄病毒的抗病毒活性提高了第二代，更紧密结合的小蛋白质。我们的目标是开发一种抗病毒小蛋白质，该抗病毒蛋白在TBE血清群中具有广泛的潜在黄病毒生物恐怖主义威胁药，包括中欧中欧tick虫 - 传播脑炎（菌株Kumlinge），Kyasanur森林疾病（FD），OMSK Hagagic Fever（OHF）和Russian Sumper Sumper Encephaliates（OHF）我们将确定MP-100对OHF-E-D3和相关TBE tbe Erogroup E-D3S的优化紧密结合类似物，并确定它们在组织培养细胞和动物中是否具有增强的抗病毒活性。抗TBE病毒小蛋白质的发展将成为针对其他黄铁病毒开发小型蛋白质的模型，这些黄体病毒也是潜在的生物恐怖威胁剂或新兴疾病，包括登革热，日本脑炎和西尼罗河。