VIRAL REPLICATION INHIBITORS TARGETED AT HIV INTEGRASE

针对 HIV 整合酶的病毒复制抑制剂

• 批准号: 2887740
• 负责人: VASU NAIR
• 金额: $ 20.08万
• 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 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887740
• 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(摘自摘要)：人类的pol1基因 免疫缺陷病毒(HIV)编码三种酶，它们对 这种病毒的复制。其中两种酶，HIV逆转 转录酶和艾滋病毒蛋白水解酶在 关于临床上有用的治疗药物的发展。第三 POL基因的酶，HIV整合酶，受到的关注要少得多。 显然，与这种酶的抑制剂有关的新信息是 在抗艾滋病毒药物研发领域具有极其重要的意义。从长远来看 这个项目的目标是对化学和酶学做出贡献。 是HIV整合酶的有效抑制剂的化合物，具有 针对艾滋病毒的细胞病变效应的治疗潜力。这 应用的重点是对序列特异性的全面研究 二核苷酸作为HIV整合酶的抑制剂。 该项目有七个具体目标。具体目标#1-#3涉及 三类化合物的设计和立体化学合成 作为HIV整合酶抑制剂的脱氧二核苷酸。其基本原理是 因为设计和选择这些用于研究的化合物的部分基础是 关于具有强大的艾滋病毒整合酶抑制活性的先导化合物。特定的 目标4涉及对目标化合物的仔细提纯和 用不同方法确定它们的结构和立体化学 光谱技术，包括多核核磁共振波谱，圆形 二向色性(CD)数据和X射线结晶学。在具体目标5中， 核苷酸间磷酸键的稳定性研究以及 核酸酶等细胞代谢酶合成5‘-磷酸单酯 和磷酸酶将被进行。在具体目标6中，协作 抑制人类免疫缺陷病毒整合酶及抑制细胞因子活性的研究 底物DNA将与整合酶结合。具体目标7是 关注全面的抗病毒研究(包括毒性研究) 最有效的HIV整合酶抑制剂及其选定的前药 表格。细胞活性物质(S)的药代动力学研究 以及细胞联合化疗研究也在计划中 选定的活性化合物。将考察协同抑制作用。