Antiviral Agents directed at West Nile Virus

描述(申请人提供)：自1999年在美国首次发现西尼罗河病毒以来，它已经超出了所有人的预期，蔓延到34个州和哥伦比亚特区。在远至南方的德克萨斯州和佛罗里达州检测到这种病毒后，病毒继续向西移动。专家认为，它最早将于明年感染加利福尼亚州。除了西尼罗河明显的健康威胁外，它也是疾控中心潜在生物恐怖威胁因子名单上的B级特工。这些事实使开发一种有效对抗西尼罗河的抗病毒药物成为当务之急。以前的研究已经提供了一个原理证明，可以开发出一种富含二硫化物的小蛋白，它将阻止壁虱传播的兰加特(LGT)病毒对细胞的感染，LGT病毒是一种自然减毒的病毒，是黄病毒属壁虱传播脑炎(TBE)血清组致病成员的模型。这种名为MP-100的微型蛋白与兰加特包膜蛋白(LgtED3)的第三结构域结合，并竞争细胞受体的结合。结果表明，MP-100蛋白能有效地阻断体外培养的Vero和LLC-MK2猴肾细胞被硬蜱携带的LGT和POW病毒感染。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。第一阶段SBIR的目标是提供一个原则证明，利用RedStorm Science公司专有的Fyrestar TM药物设计软件平台，可以开发出与西尼罗河病毒E蛋白紧密结合的微型蛋白质。在随后的第二阶段研究中，将评估由此产生的微小蛋白对蚊媒西尼罗河病毒的有效性。将针对西尼罗河包膜蛋白结构域III(WN-ED3)进行结合和结构研究。该复合体的结构将作为Fyrestar TM平台优化微型蛋白质的基础。

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.