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，估计年死亡率范围为250，000 - 500，000，包括美国约30，000例死亡和200，000例住院治疗。此外，鉴于世纪记录了三次这样的大流行，加上2009年的“猪”H1N1大流行，新出现的流感病毒株引起严重大流行的可能性非常高。其中最具破坏性的是1918年的西班牙流感，估计全世界有4000万人死亡。每年的季节性流感疫苗在预防疾病方面仅部分有效。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中仅部分有效，并且还存在耐药性问题。因此，迫切需要靶向病毒生物学未开发方面的其他抗流感治疗剂。拟议的研究旨在开发能够对抗流感病毒的新药。病毒NS 1蛋白是一个有吸引力的药物靶点，因为它是病毒复制所必需的。 vivo.抑制NS 1功能的小分子有望阻止病毒复制，从而阻止疾病。在第一阶段，开发了两个化学系列，在感染期间特异性抑制NS 1功能。这些化合物抑制细胞培养物和动物模型中的病毒复制。II期的目标是开发这些系列，为III期的IND药理学和毒理学做好准备。在目标1中，药物化学方法将用于创建高效，无毒的类似物。在目标2中，纯化的NS 1蛋白将用于生物化学测定，以确定新合成的类似物的结合常数，X射线晶体学将用于了解配体-药物复合物的结构。这些方法将支持更好的NS 1抑制剂的设计。在目的3中，将根据几个标准评估类似物，包括抗病毒活性、细胞毒性、细胞干扰素的诱导和体外ADME性质。目标4将在BALB/c小鼠体内试验中达到高潮，包括MTD、PK和疗效研究。

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.