Discovery of West Nile Virus Protease Inhibitors

西尼罗河病毒蛋白酶抑制剂的发现

• 批准号: 7107091
• 负责人: Sherri Zimmerman Millis
• 金额: $ 3.93万
• 依托单位: HAWAII BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2006-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107091
• 关键词: Flaviviridae; active sites; endopeptidases; library; protease inhibitor; proteins

DESCRIPTION (provided by applicant): The strain of West Nile virus now endemic in the continental United States is more virulent than the virus originally isolated in Africa and is classified as a category B priority pathogen by the NIAID. In only six years, it has spread throughout the continental United States, resulting in high morbidity and mortality. Last year, of the 2,539 cases reported to the CDC, nearly half of the patents had neuroinvasive symptoms. There is currently no vaccine or drug that combats the West Nile virus infection and only symptomatic treatment is available. Our ultimate goal is to develop a prophylactic or therapeutic treatment for this disease. To accomplish this, we will develop methods for the identification of compounds that inhibit the West Nile viral NS3 protease. The protease is a key enzyme in viral maturation and inhibition of flavivirus protease has been shown to dramatically reduce viral replication. Structure based drug design will provide a rapid path to potent and virus specific protease inhibitors. The crystal structure of this protease in the presence and absence of known peptide based inhibitors will be determined in an effort to characterize the active site. We will virtually screen the active site with a chemical library. Careful attention will be made to the composition of the library to ensure enrichment with diverse, pharmacologically active, lead-like compounds. A biochemical assay will be developed that has a wide range of sensitivity that can be used in the identification of weak binding initial hits from our virtual screen as well as to measure small changes in inhibition as we optimize these hits in future research. Compounds that are selected in the virtual screen and are active in the biochemical assay will be cocrystallized with the protease, giving us a clear picture of the compound's fit into the active site. This will position us to rapidly identify the best candidates from the active compounds and subsequent optimization in phase 2 research.

描述（由申请人提供）：目前在美国大陆流行的西尼罗河病毒株比最初在非洲分离出的病毒毒性更强，被 NIAID 列为 B 类优先病原体。仅仅六年时间，它就蔓延到整个美国大陆，导致高发病率和死亡率。去年，在向 CDC 报告的 2,539 例病例中，近一半患者有神经侵袭性症状。目前尚无针对西尼罗河病毒感染的疫苗或药物，只能进行对症治疗。我们的最终目标是开发针对这种疾病的预防或治疗方法。为了实现这一目标，我们将开发鉴定抑制西尼罗河病毒 NS3 蛋白酶的化合物的方法。该蛋白酶是病毒成熟的关键酶，抑制黄病毒蛋白酶已被证明可以显着减少病毒复制。基于结构的药物设计将为有效的病毒特异性蛋白酶抑制剂提供快速途径。在存在和不存在已知的基于肽的抑制剂的情况下，将确定该蛋白酶的晶体结构，以努力表征活性位点。我们将使用化学库虚拟筛选活性位点。我们将仔细关注文库的组成，以确保富集多种具有药理活性的先导化合物。将开发一种具有广泛灵敏度的生化测定，可用于从我们的虚拟屏幕中识别弱结合的初始命中，并在我们在未来的研究中优化这些命中时测量抑制的微小变化。在虚拟屏幕中选择的并且在生化测定中具有活性的化合物将与蛋白酶共结晶，从而使我们清楚地了解该化合物与活性位点的配合情况。这将使我们能够从活性化合物中快速识别出最佳候选化合物，并在第二阶段研究中进行后续优化。