Novel anti-viral agents to treat influenza

描述（由申请人提供）：每年流感流行影响约5% - 15%的世界人口，估计每年死亡人数在250,000 - 500,000之间，其中包括美国约30,000人死亡和200,000人住院治疗。此外，一种新出现的流感病毒毒株引起严重大流行的可能性非常高，因为在20世纪记录了三次这种大流行，加上2009年的“猪”H1N1大流行。其中最具破坏性的是1918年的西班牙流感，据估计全世界有4000万人死亡。每年接种的季节性流感疫苗只能部分有效地预防疾病。同样，目前可用的抗流感药物，如金刚烷胺和奥司他韦，在治疗预防方面仅部分有效，而且还存在耐药性问题。因此，迫切需要针对病毒生物学未开发方面的其他抗流感疗法。拟议的研究旨在开发对抗流感病毒的新药。病毒NS1蛋白是一种有吸引力的药物靶点，因为它是病毒复制所必需的

DESCRIPTION (provided by applicant): Yearly influenza epidemics affect about 5 - 15% of the world's population and estimates of annual mortality range from 250,000 - 500,000, including approximately 30,000 deaths and 200,000 hospitalizations in the United States. In addition, the likelihood of a severe pandemic caused by a newly emergent strain of influenza virus is very high, given that three such pandemics were recorded in the 20th century, plus the "swine" H1N1 pandemic of 2009. The most devastating of these, the 1918 Spanish influenza, was associated with an estimated 40 million deaths worldwide. The annual vaccine for seasonal influenza is only partially effective in prevention of disease. Likewise, currently available anti-influenza drugs such as amantadine and oseltamivir are only partially effective in treatment prophylaxis, and also suffer from problems of drug resistance. Therefore, there is an urgent need for additional anti-influenza therapeutics that target unexploited aspects of viral biology. The proposed studies are directed at developing new drugs that can combat influenza virus. The viral NS1 protein is an attractive drug target because it is essential for virus replication in vivo. Small molecules that inhibit NS1 function are expected to block virus replication, and hence disease. During Phase I, two chemical series were developed that specifically inhibit NS1 function during infection. These compounds inhibit virus replication in cell culture and an animal model. The goal for Phase II is to develop these series to be ready for IND-enabling pharmacology and toxicology in Phase III. In Aim 1, medicinal chemistry approaches will be used to create highly potent, non-toxic analogs. In Aim 2, purified NS1 protein will be used in biochemical assays to determine binding constants for the newly synthesized analogs, and X-ray crystallography will be employed to understand the structure of ligand-drug complexes. These methods will support the design of better NS1 inhibitors. In Aim 3, the analogs will be assessed according to several criteria including antiviral activity, cytotoxicity, induction of cellular interferon, and in vitro ADME properties. Aim 4 will culminate with in vivo testing in BALB/c mice, including MTD, PK and efficacy studies.