NMR AND DESIGN OF ANTISENSE AND RIBOZYME AGENTS TO HIV

多维1H同核和异核核磁共振，分子 模型、分子动力学和微扰自由能计算 将被用于定义反义和反义的三维结构 金属核酶寡核苷酸类似物(包括顺铂) 二硫代磷酸寡核苷酸试剂和核酸试剂复合体 以人类免疫缺陷(艾滋病)病毒为目标。 非对映异构体纯甲基膦和硫代磷酸盐及新型 将合成二硫代磷酸寡核苷酸类似物，并 它们与互补单环的络合物的三维结构 而双链寡核苷酸将被确定为理解 也将获得体外和体内的生物活性。 各种RNA和DNA结合和基因调节剂将 用已有的有机合成方法合成的。我们将采取一项 靶向代理的合理设计的综合方法 人类免疫缺陷病毒(HIV)利用高分辨率 核磁共振(核磁共振)波谱，计算 生物化学和生物分子的分子模拟。这一支持将 为NSF生物设施的研究基地提供资金 以双分子核磁共振、结构与设计及核磁共振结构为中心 美国国立卫生研究院指定的艾滋病研究中心的生物学核心已经 成立于普渡大学。核磁共振光谱学将提供一个重要的探针 生物大分子的分子结构和动力学。 最终，我们希望合理地设计和构建能够 对HIV基因转录提供潜在的不可逆转的抑制。

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.