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Structural basis for influenza amantadine-resistance

流感金刚烷胺耐药的结构基础

基本信息

批准号：
7880726
负责人：
JAMES Jeiwen CHOU
金额：
$ 31.97万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The influenza pandemics have long been a serious global health threat responsible for approximately 20,000 deaths per year in the US. It has been established that small H+ selective channels M2 and BM2 from influenza A and B virus play a critical role in viral replication and thus are effective targets for anti-influenza therapy. Amantadine is a licensed anti-influenza A drug that functions by inhibiting the pH activation of the M2 channel. However a number of M2 variants, as well as the BM2 channel of influenza B can escape the effect of amantadine, leading to the amantadine-resistance of these viruses. We propose to provide the atomic details of H+ gating and drug interaction of these small channels for understanding the mechanisms by which some influenza strains are resistant to amantadine. Initially we will solve the high resolution structure of the M2 H+ channel of influenza A virus in the closed state at pH 7.2. A new method has been devised to facilitate structure determination by solution NMR, which incorporates the dipolar couplings for acquiring orientation parameters and lipid/detergent bilayered micelles to enable characterization of atomic structures in a near lipid-bilayer environment. We will also solve the channel structure in the open state at pH 5.2 to delineate changes in conformation and dynamics that are coupled to low-pH activation. To understand the mechanism of amantadine inhibition, we will solve the channel structures, both closed and open, in the presence of drug binding. The sites of amantadine interaction in the channel will also be located. In parallel, the structures of the known amantadine-resistant variants of M2 will be examined for direct comparison to elucidate mechanisms of channel blocking. Similar studies will be done for the BM2 channel, which functions similarly to M2 but is resistant to amantadine. Structural details of the potential amantadine-BM2 interaction that does not block the channel will also be explored. The results will lay a solid foundation for our long- range goal of finding a true blocker of H+ channels for anti-influenza treatment.

描述(申请人提供)：流感大流行长期以来一直是严重的全球健康威胁，每年导致美国约20,000人死亡。甲型和乙型流感病毒的小分子H+选择性通道M2和BM2在病毒复制中起关键作用，是抗流感治疗的有效靶点。金刚烷胺是一种获得许可的抗甲型流感药物，其作用是通过抑制M2通道的pH激活来发挥作用。然而，一些M2变异体以及B型流感的BM2通道可以逃脱金刚烷胺的影响，导致这些病毒对金刚烷胺产生抗药性。我们建议提供这些小通道的H+门控和药物相互作用的原子细节，以了解一些流感病毒株对金刚烷胺耐药的机制。首先，我们将解决甲型流感病毒M2 H+通道在pH 7.2的关闭状态下的高分辨结构。设计了一种新的方法，以便于通过溶液核磁共振确定结构，该方法结合了用于获得取向参数的偶极耦合和脂类/去污剂双层胶束，从而能够在近脂类双层环境中表征原子结构。我们还将解决在pH 5.2的开放状态下的通道结构，以描绘与低pH激活相耦合的构象和动力学的变化。为了了解金刚烷胺的抑制机制，我们将解决存在药物结合时的通道结构，包括闭合和开放。还将定位通道中金刚烷胺相互作用的位置。同时，我们将检查已知的金刚烷胺耐药M2变异体的结构，以进行直接比较，以阐明通道阻断的机制。将对BM2通道进行类似的研究，该通道的功能类似于M2，但对金刚烷胺具有抗药性。还将探索不阻断该通道的潜在金刚烷胺-BM2相互作用的结构细节。这一结果将为我们寻找真正的H+通道阻滞剂用于抗流感治疗的长期目标奠定坚实的基础。