DESIGN OF SELECTIVE INHIBITORS OF DNA POLYMERASES

DNA 聚合酶选择性抑制剂的设计

• 批准号: 3270651
• 负责人: George E Wright
• 金额: $ 14.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-12-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3270651
• 关键词: DNA directed DNA polymerase; HeLa cells; aminopurine; antineoplastics; antiviral agents; chemical structure function; deoxyguanosine; deoxyribonucleoside triphosphate; deoxyribonucleosides; deoxyribonucleotides; drug design /synthesis /production; drug screening /evaluation; growth factor; herpes simplex virus 1; organic chemicals; tissue /cell culture

The long range goal of this research is to probe the active site regions of replicative DNA polymerases and to uncover similarities and differences among them by the use of selective, active-site-directed inhibitors. The ability of these and related compounds to stop the growth of cells involved in disease states may be of value in designing drugs for the treatment of cancer and viral infections. The general class of inhibitors that are the subject of this work are N2-substituted 2-aminopurines, their 2'-deoxyribonucleosides and 5'-triphosphates of the latter. Techniques of organic synthesis and structure determination, separation methods, enzymology and cell culture will be employed to achieve the following specific aims: 1) synthesis and testing of deoxyribonucleotide analogs as inhibitors of and substrates for mammalian cell DNA polymerase alpha to explore the structure of the active site of the enzyme; 2) preparation and exploitation of inhibitor-based affinity columns for the purification of DNA polymerase alpha; 3) examination of the mechanism of cytotoxicity of inhibitors toward mammalian cells, and their potential anabolism or catabolism by cellular enzymes; and 4) synthesis and testing of N2-substituted-2'-deoxyguanosine 5'-triphosphates for inhibition of Herpes simplex virus type 1 DNA polymerase, and antiviral activity of suitable base or deoxyribonucleoside derivatives.

这项研究的远距离目标是探究 复制DNA聚合酶并发现相似性和差异 其中通过使用选择性，主动站点定向的抑制剂。 这 这些和相关化合物阻止细胞生长的能力 在疾病状态中，在设计药物治疗药物方面可能很有价值 癌症和病毒感染。 这项工作主题的一般抑制剂类是 N2取代的2-氨基嘌呤，其2'-脱氧核糖核苷和 后者的5'-三磷酸盐。 有机合成技术和 结构确定，分离方法，酶学和细胞培养 将采用以下特定目标：1）合成和 测试脱氧核糖核苷酸类似物作为抑制剂和底物的测试 哺乳动物细胞DNA聚合酶α以探索活性的结构 酶部位； 2）基于抑制剂的准备和开发 纯化DNA聚合酶α的亲和力柱； 3） 检查抑制剂对哺乳动物的细胞毒性机制 细胞及其潜在的合成代谢或细胞酶分解代谢；和 4）N2-取代-2'-脱氧鸟苷的合成和测试 5'-三磷酸盐抑制单纯疱疹病毒1型DNA 合适碱或脱氧核苷的聚合酶和抗病毒活性 衍生物。