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