NMR AND DESIGN OF ANTISENSE AND RIBOZYME AGENTS TO HIV

多维1H同向和异向NMR，分子 模拟、分子动力学和微扰自由能计算 将用于定义反义和反义寡核苷酸的三维结构， 核酶寡核苷酸类似物、金属（包括顺铂） 二硫代磷酸寡核苷酸试剂和核酸-试剂复合物 针对人体免疫缺陷（艾滋病）病毒。 非对映异构纯的甲基膦酸酯和硫代磷酸酯以及新的 将合成二硫代磷酸酯寡核苷酸类似物， 三维结构的互补单， 和双链寡核苷酸将被确定为了解 还将获得体外和体内生物活性。 各种RNA和DNA结合和基因调节剂将被使用。 使用已建立的有机合成方法合成。 我们将采取一个 合理设计目标制剂的综合方法 人体免疫缺陷病毒（艾滋病毒）的高分辨率 核磁共振（NMR）光谱学，计算的 生物化学和生物分子的分子建模。 这种支持将 为NSF生物设施提供研究基地的资金 双分子核磁共振中心、结构与设计及核磁共振结构 美国国立卫生研究院指定的艾滋病研究中心的生物核心已经 在Purdue成立。 核磁共振光谱学将提供一个重要的探测器 生物大分子的分子结构和动力学。 最终，我们希望理性地设计和构建代理， 提供潜在的不可逆的HIV基因转录抑制。

Multi-dimensional 1H homonuclear and heteronuclear NMR, molecular modeling, molecular dynamics and perturbational free energy calculations will be used to define the three-dimensional structure of antisense and ribozyme oligonucleotide analogues, metal (including cis-platinum) dithiophosphate oligonucleotide agents and nucleic acid-agent complexes targeted towards the human immunodeficiency (AIDS) virus. Diasteromerically pure methylphosphonate and phosphorothioates and novel phosphorodithioates oligonucleotide analogues will be synthesized and the three-dimensional structure of their complexes with complementary single- and double-stranded oligonucleotides will be determined to understand the in vitro and in vivo biological activities that will also be obtained. Various RNA and DNA binding and gene regulatory agents will be synthesized using established synthetic organic methods. We will take an integrated approach towards the rational design of agents targeted towards the human immunodeficiency virus (HIV) utilizing high resolution nuclear magnetic resonance (NMR) spectroscopy, computational biochemistry, and molecular modeling of biomolecules. This support will provide funding of the research base for an NSF Biological Facilities Center in Bimolecular NMR, Structure and Design and the NMR Structural Biology Core of an NIH designated AIDS Research Center already established at Purdue. NMR spectroscopy will provide an important probe of the molecular structure and dynamics of biological macromolecules. Ultimately we hope to rationally design and construct agents that will provide potential irreversible inhibition of HIV gene transcription.