Development of drugs that target the M2 proton channel from the influenza A Virus

开发针对甲型流感病毒 M2 质子通道的药物

• 批准号: 7813771
• 负责人: WILLIAM DEGRADO
• 金额: $ 162.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813771
• 关键词: Acute; Address; Affinity; Amantadine; Amantadine resistance; Animal Model; Antiviral Agents; Arts; Centers for Disease Control and Prevention (U.S.); Chemicals; Child; Complex; Data Analyses; Development; Diamond; Drug Delivery Systems; Drug Design; Drug Formulations; Drug Kinetics; Drug resistance; Evaluation; FDA approved; Generations; Goals; Hand; Health; Human; In Vitro; Individual; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Lead; Left; Libraries; Marketing; Metabolic; Methodology; Neuraminidase; Nursing Homes; Oseltamivir; Pharmaceutical Preparations; Pharmacology and Toxicology; Population; Property; Prophylactic treatment; Proteins; Protons; Recommendation; Research Personnel; Seasons; Sodium Chloride; Structure; Toxic effect; Viral; Viral Proteins; Virus; anti-influenza drug; base; design; drug development; flu; high risk; high throughput screening; in vitro Assay; in vivo; influenza outbreak; influenza virus strain; influenzavirus; inhibitor/antagonist; molecular dynamics; mutant; novel; pre-clinical; prevent; programs; protein structure; scale up; structural biology

DESCRIPTION (provided by applicant): Viral influenza, particularly the H5N1 strain of influenza A virus, is a serious threat to human health. Currently there are two different classes of approved anti-influenza drugs, which target different viral proteins: amantadine targets a protein called the M2 proton channel, while Tamiflu (oseltamivir) targets neuraminidase. In the last flu season, most strains of the influenza virus (including H5N1) have become resistant to the amantadine class of drugs, causing the CDC to issue a recommendation to discontinue their use. Thus, there is an urgent need for a second-generation amantadine-like drug that will be useful prophylactically against new mutant strains of the virus including H5N1. We will take a variety of approaches to design second generation M2 blockers. To accomplish this goal a team of investigators has been assembled (DeGrado, Cristian, Diamond, Klein, Lamb, Paessler, Pinto, Winkler), each with special expertise. This team, led by DeGrado, will build on important preliminary results to design second generation M2 blockers. To this end, we have crystallized the proton channel, both in the presence and absence of amantadine, and the structures will be solved in Aim 1. The availability of crystal structures of the protein will be used in structure-based drug design in Aim 2. In parallel, state-of-the-art high throughput screening methodologies will be employed to discover novel lead inhibitors (Aim 3). The in vitro potency of the lead compounds will be optimized in Aim 4. The goal of Aims 5 and 6 is to identify compounds or compound classes that demonstrate antiviral in vivo efficacy against M2 without obvious toxicity. These studies will evaluate acute toxicity, pharmacokinetic properties, metabolic stability and in vivo efficacy of the discovery lead compounds. The results from these studies will be used to select a few lead compounds for more complete drug development evaluations suitable for regulatory submission (Aims 7, 8). The ultimate goal of the program is to complete all studies to enable filing an IND. In addition to overseeing the overall program, DeGrado's group will be responsible for structural biology and the chemical aspects of the project.

描述（申请人提供）：病毒性流感，特别是甲型流感病毒H5N1株，对人类健康构成严重威胁。目前已批准的抗流感药物有两类，它们针对不同的病毒蛋白：金刚烷胺针对一种称为 M2 质子通道的蛋白质，而达菲（奥司他韦）针对神经氨酸酶。在上一个流感季节，大多数流感病毒株（包括 H5N1）已经对金刚烷胺类药物产生了耐药性，导致 CDC 发出停止使用此类药物的建议。因此，迫切需要一种第二代金刚烷胺类药物，可用于预防包括 H5N1 在内的新病毒突变株。我们将采取多种方法来设计第二代M2阻断剂。为了实现这一目标，我们组建了一个调查小组（DeGrado、Cristian、Diamond、Klein、Lamb、Paessler、Pinto、Winkler），每个人都拥有特殊的专业知识。该团队由 DeGrado 领导，将在重要的初步成果的基础上设计第二代 M2 阻断剂。为此，我们在存在和不存在金刚烷胺的情况下使质子通道结晶，并且将在目标 1 中解析结构。蛋白质晶体结构的可用性将用于目标 2 中基于结构的药物设计同时，将采用最先进的高通量筛选方法来发现新型先导抑制剂（目标 3）。目标 4 中将优化先导化合物的体外效力。目标 5 和 6 的目标是鉴定能够证明对 M2 具有体内抗病毒功效且无明显毒性的化合物或化合物类别。这些研究将评估所发现的先导化合物的急性毒性、药代动力学特性、代谢稳定性和体内功效。这些研究的结果将用于选择一些先导化合物，以进行适合监管提交的更完整的药物开发评估（目标 7、8）。该计划的最终目标是完成所有研究以提交 IND。除了监督整个项目外，DeGrado 的团队还将负责该项目的结构生物学和化学方面。