RNA-DNA HYBRID BINDING AGENTS

RNA-DNA 混合结合剂

• 批准号: 3143174
• 负责人: Fusao None Takusagawa
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3143174
• 关键词: AIDS; antiAIDS agent; crystallization; drug design /synthesis /production; drug interactions; enzyme inhibitors; human immunodeficiency virus; nucleotide analog; virus DNA; virus RNA

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.

本研究项目的主要目标是设计和合成 RNA-DNA杂合剂，可抑制逆转录病毒的RNase活性 DNA聚合酶 因此，这样的试剂将是可能的治疗剂 人类免疫缺陷病毒（HIV）。 逆转录病毒的一个特征性功能， 在正常的真核细胞中， 病毒复制阶段。 如果代理人被设计成只与 RNA-DNA杂交，但不能与DNA或RNA杂交，这类药物就能抑制 特别是逆转录病毒DNA聚合酶的RNase H活性，和 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。 这一假设已经通过分子力学计算进行了验证， 放线菌素类似物和一种 小RNA-DNA杂合体。 分子力学计算的结果 表明该类似物可以与RNA-DNA杂合体结合。 因此，这 放线菌素类似物是一种可以终止降解活性的分子 逆转录病毒RNA酶H通过优先结合RNA-DNA杂合体。 这将抑制病毒复制。 因此，该化合物应 研究和测试作为一种可能的治疗剂对艾滋病。