Antiviral Agents directed at West Nile Virus

针对西尼罗河病毒的抗病毒药物

• 批准号: 6644585
• 负责人: STEVEN T WHITTEN
• 金额: $ 24.89万
• 依托单位: REDSTORMSCIENTIFIC, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6644585
• 关键词: Tick borne encephalitis virus; West Nile virus; X ray crystallography; antiviral agents; biotherapeutic agent; computer simulation; drug design /synthesis /production; nuclear magnetic resonance spectroscopy; peptides; protein binding; protein protein interaction; protein structure; virus envelope

DESCRIPTION (provided by applicant): The West Nile virus has surpassed all expectations spreading to 34 states and the District of Columbia since it was first detected in the United States in 1999. Having already been detected as far south as Texas and Florida, the virus continues to move westward. Experts believe it will infect California as early as next year. In addition to West Nile's obvious health threats, it is also a B class agent on the CDC's list of potential bioterrorist threat agents. These facts make the development of an anti-viral agent effective against West Nile a high priority. 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 the tick-borne 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. The miniprotein termed MP-100 binds to domain III of the Langat envelope protein (LgtED3) and competes for cell receptor binding. The miniprotein MP-100 was shown to block infection of Vero and LLC-MK2 monkey kidney cell cultures by tick-borne Lgt and Powassan (POW) viruses. Further studies indicated significant antiviral activity in a mouse animal model. The goal of this Phase I SBIR is to provide a proof-of-principle that a miniprotein can be developed that binds tightly to West Nile virus E protein using RedStorm Scientific's proprietary Fyrestar TM drug design software platform. In a subsequent Phase II study the effectiveness of the resulting miniproteins against the mosquito-borne West Nile virus will be assessed. Binding and structural studies will be carried out against the West Nile envelope protein Domain III (WN-ED3). The structure of the complex will serve as a basis for the optimization of the miniprotein by the Fyrestar TM platform.

描述（由申请人提供）：自1999年在美国首次发现西尼罗河病毒以来，该病毒已超出所有预期，蔓延至34个州和哥伦比亚特区。这种病毒已经在南至德克萨斯州和佛罗里达的地方被发现，并继续向西移动。专家认为，最早明年它就会感染加州。除了西尼罗河病毒明显的健康威胁外，它也是疾病预防控制中心潜在生物恐怖威胁因子名单上的B级因子。这些事实使得开发一种有效对抗西尼罗河病毒的抗病毒药物成为高度优先事项。 先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，其将阻断蜱传Langat（Lgt）病毒对细胞的感染，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。称为MP-100的微蛋白结合Langat包膜蛋白（LgtED 3）的结构域III，并竞争细胞受体结合。微蛋白MP-100可阻断蜱传Lgt和Powassan（POW）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显著的抗病毒活性。该I期SBIR的目标是提供一个原理证明，即可以使用RedStorm Scientific专有的Fyrestar TM药物设计软件平台开发与西尼罗河病毒E蛋白紧密结合的微型蛋白。在随后的第二阶段研究中，将评估所得微蛋白对蚊子传播的西尼罗河病毒的有效性。结合和结构研究将针对西尼罗河病毒包膜蛋白结构域III（WN-ED 3）进行。复合物的结构将作为Fyrestar TM平台优化微蛋白的基础。