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（改编自摘要）：人类的pol基因 免疫缺陷病毒（HIV）编码三种酶， 这种病毒的复制 其中两种酶， 转录酶和HIV蛋白酶，已经受到相当大的关注， 临床上有用的治疗剂的发展的术语。 第三 pol基因的酶HIV整合酶受到的关注要少得多。 显然，有关这种酶的抑制剂的新信息是 在抗艾滋病毒药物发现领域至关重要。 长期 该项目的目标是促进化学和酶学， 本发明涉及作为HIV整合酶的有效抑制剂并具有 抗HIV致细胞病变作用的治疗潜力。 这 应用集中在序列特异性的综合研究上。 作为HIV整合酶抑制剂的二核苷酸。 该项目有七个具体目标。 具体目标#1-#3涉及 设计并立体化学合成了三种不同结构的 作为HIV整合酶抑制剂的靶向脱氧二核苷酸。 的理由 设计和选择这些化合物进行研究的部分基础是 具有强效HIV整合酶抑制活性的先导化合物。 具体 目标#4涉及目标化合物的仔细纯化， 通过各种方法建立它们结构和立体化学 光谱技术，包括多核NMR光谱，循环 二向色性（CD）数据和X射线晶体学。 具体目标#5 核苷酸间磷酸键的稳定性研究以及 5 ′-磷酸单酯通过细胞代谢酶如核酸酶 和磷酸酶。 在具体目标#6中，合作 HIV整合酶的抑制作用和HIV整合酶的抑制作用的研究 将进行底物DNA与整合酶的结合。 具体目标#7 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 forms. 细胞活性最高化合物的药代动力学研究 也计划进行细胞联合化疗研究， 选择活性化合物。 将检查协同抑制。