RNA-DNA HYBRID BINDING AGENTS

本研究项目的主要目标是设计和合成 可能抑制逆转录病毒核糖核酸酶活性的RNA-DNA杂交剂 DNA聚合酶。因此，这种药剂可能是一种治疗剂。 抗人类免疫缺陷病毒(HIV)。 逆转录病毒的一个特征功能，通常不是 在正常的真核细胞中发现的，是一种长RNA-DNA杂交的产物 病毒复制阶段。如果设计的代理仅绑定到 RNA-DNA杂交体，但不能到DNA或RNA，这样的试剂就能抑制 特别是逆转录病毒DNA聚合酶的RNaseH活性，以及 因此会抑制病毒复制。放线菌素类似物可能是 能够与RNA-DNA杂交体结合。 这一假设已通过分子力学计算得到验证，该计算使用 放线菌素类似物与α-氨基丁酸络合物的模型结构 小RNA-DNA杂交种。分子力学计算的结果 提示该类似物可以与RNA-DNA杂交物结合。因此，这一点 放线菌素类似物是一种可以阻止降解活性的分子。 通过优先与RNA-DNA杂交物结合来抑制逆转录病毒RNaseH。 这将抑制病毒复制。因此，化合物应该是 作为一种可能的艾滋病治疗剂进行了调查和测试。

The primary goal of this research project is the design and synthesis of RNA-DNA hybrid agent, which might inhibit the RNase activity of retroviral DNA polymerase. Thus, such a agent would be a possible therapeutic agent against human immunodeficiency virus (HIV). One characteristic function of the retroviruses, which is generally not found in normal eukaryotic cells, is production of a long RNA-DNA hybrid in the viral replication phase. If agents are designed which bind only to the RNA-DNA hybrid, but not to DNA or RNA, such agents will be able to inhibit specifically the RNase H activity of retroviral DNA polymerase, and therefore will suppress viral replication. Actinomycin analogue might be able to bind to an RNA-DNA hybrid. This hypothesis has been tested by a molecular mechanics calculation using a model structure of the complex between the actinomycin analogue and a small RNA-DNA hybrid. The results of the molecular mechanics calculation suggest that the analogue can bind to the RNA-DNA hybrid. Thus, this actinomycin analogue is a molecule which may stop the degradative activity of retroviral RNase H by binding preferentially to the RNA-DNA hybrid. This would suppress viral replication. The compound should therefore be investigated and tested as a possible therapeutic agent against AIDS.