ISOLATION OF BULK DEOXYNUCLEOSIDES FOR AIDS DRUGS

用于艾滋病药物的大量脱氧核苷的分离

• 批准号: 3506042
• 负责人: JOSEPH A TOCE
• 金额: $ 36.83万
• 依托单位: RELIABLE BIOPHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1990-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3506042
• 关键词: DNA; antiAIDS agent; antiviral agents; chromatography; deoxyadenosines; deoxycytidine; deoxyribonuclease I; deoxyribonucleosides; high performance liquid chromatography; ion exchange chromatography; phosphodiesterase I; trout /salmon; zidovudine

Deoxynucleosides are currently playing an increasing role in medicine. Several experimental anti-viral AIDS drugs (AZT, DCC, AND DDA) are chemically modified deoxynucleosides. These drugs are expensive due to the unavailability of deoxynucleosides at reasonable costs. Deoxynucleosides are also in demand as nutrients in mammalian tissue cultures used to produce monoclonal antibodies and other medically significant blood products. A minor modified component of eukaryotic DNA is 5-methyldeoxycytosine. It is needed for the study of gene expression control and for chemical synthesis of modified DNA fragments used in recombinant DNA technology. Considering the need for anti-viral drugs and cloned blood products and the importance of time and cost, and Phase II research program is proposed for the immediate availability of specific deoxynucleosides. The proposed research consists of four specific segments: a) optimization of the enzymatic hydrolysis reaction while reducing the level of deamination in the deoxynucleoside mixture, b) scaling up the ion-exlusion column and developing the secondary chromatographic column required for final purification of each deoxynucleoside, c) finalize procedures to product crystalline deoxynucleosides and d) establish quality control specifications and explore methods for purifying 5- methyldeoxycytosine. Cost analysis indicates that optimization of the Phase I innovations will result in a significant price reduction of deoxynucleosides.

目前，脱氧核苷在以下方面发挥着越来越重要的作用： 药品。 几种实验性抗病毒艾滋病药物（AZT、DCC、 和DDA）是化学修饰的脱氧核苷。 这些药物是 由于脱氧核苷在 合理的成本。 脱氧核苷作为营养素也有需求 在用于生产单克隆抗体的哺乳动物组织培养物中 和其他具有医学意义的血液制品。 稍作修改 真核DNA的成分是5-甲基脱氧胞嘧啶。 需要的是 用于基因表达控制研究和化学合成 用于重组 DNA 技术的修饰 DNA 片段。 考虑抗病毒药物和克隆血液制品的需求 以及时间和成本的重要性以及第二阶段研究计划 建议立即提供特定的 脱氧核苷。 拟议的研究包括四个具体内容 部分：a) 酶促水解反应的优化 同时降低脱氧核苷中的脱氨基水平 混合物，b) 扩大离子排除柱并开发 最终纯化所需的二级色谱柱 每个脱氧核苷，c）最终确定产品程序 结晶脱氧核苷和 d) 建立质量控制 规范并探索纯化 5- 的方法 甲基脱氧胞嘧啶。 成本分析表明，优化 第一阶段的创新将带来巨大的代价 脱氧核苷的减少。