VIRAL REPLICATION INHIBITORS TARGETED AT HIV INTEGRASE

针对 HIV 整合酶的病毒复制抑制剂

• 批准号: 6171037
• 负责人: VASU NAIR
• 金额: $ 20.68万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171037
• 关键词: X ray crystallography; antiAIDS agent; circular dichroism; drug design /synthesis /production; drug discovery /isolation; enzyme inhibitors; human immunodeficiency virus; integrase; nuclear magnetic resonance spectroscopy; pharmacokinetics

DESCRIPTION (adapted from the Abstract): The pol gene of the human immunodeficiency virus (HIV) encodes three enzymes which are critical for the replication of this virus. Two of these enzymes, HIV reverse transcriptase and HIV protease, have received considerable attention in terms of the development of clinically useful therapeutic agents. The third enzyme of the pol gene, HIV integrase, has received much less attention. Clearly, new information pertaining to inhibitors of this enzyme is of critical importance in the anti-HIV drug discovery area. The long term goals of this project are to contribute to the chemistry and enzymology of compounds that are potent inhibitors of HIV integrase and that have useful therapeutic potential against the cytopathic effect of HIV. This application is focused on a comprehensive study of sequence specific dinucleotides as inhibitors of HIV integrase. The project has seven specific aims. Specific Aims #1-#3 are concerned with the design and stereochemical synthesis of three classes of deoxydinucleotides targeted as inhibitors of HIV integrase. The rationale for the design and selection of these compounds for study is based in part on lead compounds with potent HIV integrase inhibitory activity. Specific Aim #4 involves careful purification of the target compounds and establishment of their structure and stereochemistry by various spectroscopic techniques including multinuclear NMR spectroscopy, circular dichroism (CD) data, and X-ray crystallography. In Specific Aim #5, stability studies of the internucleotide phosphate bonds as well as the 5'-phosphate monoesters by cellular metabolizing enzymes such as nucleases and phosphatases will be conducted. In Specific Aim #6, collaborative studies on the inhibition of HIV integrase and on the inhibition of the binding of substrate DNA with integrase will undertaken. Specific Aim #7 is concerned with comprehensive antiviral studies (including toxicity studies) of the most potent inhibitors of HIV integrase and their selected pro-drug forms. Pharmacokinetic studies of the cellularly most active compound(s) are also planned, as are cellular combination chemotherapeutic studies with selected active compounds. Synergistic inhibition will be examined.

描述（根据摘要改编）：人类的pol基因 免疫缺陷病毒（HIV）编码三种酶 该病毒的复制。 这些酶中的两个，艾滋病毒反向 转录酶和艾滋病毒蛋白酶在 临床上有用的治疗剂的发展条款。 第三 POL基因的酶HIV整合酶的注意力较少。 显然，与该酶抑制剂有关的新信息是 在抗HIV药物发现区域中至关重要。 长期 该项目的目标是为化学和酶学做出贡献 具有有效艾滋病毒整合酶抑制剂并且具有有用的化合物 针对HIV的细胞质作用的治疗潜力。 这 应用集中于对序列特定的全面研究 二核苷酸作为HIV整合酶的抑制剂。 该项目具有七个特定目标。 特定目标＃1-＃3与 三类的设计和立体化学合成 脱氧核苷酸靶向HIV整合酶的抑制剂。 理由 对于这些化合物的设计和选择，用于研究的部分是基于 在具有有效HIV积分酶抑制活性的铅化合物上。 具体的 AIM＃4涉及仔细纯化目标化合物，并且 建立其结构和立体化学 光谱技术，包括多核NMR光谱，循环 二分（CD）数据和X射线晶体学。 在特定的目标＃5中 核苷酸间磷酸键的稳定性研究以及 通过细胞代谢酶（例如核酸酶）的5'-磷酸单植物 将进行磷酸酶。 在特定的目标＃6中，协作 研究抑制艾滋病毒整合酶和抑制 将进行底物DNA与整合酶的结合。 特定目标＃7是 与全面的抗病毒研究有关（包括毒性研究） 最有效的艾滋病毒整合酶及其选定的pro-prug的抑制剂 表格。 细胞最活跃化合物的药代动力学研究 还计划了，以及细胞组合化学治疗研究 选定的活性化合物。 将检查协同抑制作用。