Viral Replication Inhibitors Targeted at HIV Integrase

针对 HIV 整合酶的病毒复制抑制剂

• 批准号: 6598072
• 负责人: VASU NAIR
• 金额: $ 23.23万
• 依托单位: UNIVERSITY OF GEORGIA
• 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 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6598072
• 关键词: X ray crystallography; antiAIDS agent; drug design /synthesis /production; enzyme inhibitors; human immunodeficiency virus; integrase; nuclear magnetic resonance spectroscopy; pharmacokinetics; tissue /cell culture

The pol gene of HIV encodes three key enzymes for viral replication. Two of these enzymes, HIV reverse transcriptase (RT) and HIV protease; have received considerable attention in terms of clinically useful inhibitors. In contrast, the third enzyme of the pol gene, HIV integrase, has received much less attention. There are no drugs in clinical use for AIDS where the mechanism of action is inhibition of HIV integrase. The integration process is essential for HIV replication and there is no functional equivalent of HIV integrase in human cells. It is clear that new information on inhibitors of this enzyme is of critical importance in the anti-HIV drug discovery area. The long-term objectives of this research project are the discovery of therapeutically useful inhibitors of HIV integrase. Utilizing knowledge on the mechanism of action of HIV integrase, two potent inhibitors of HIV-1 integrase have been discovered in the current grant period . These inhibitors are conceptually novel dinucleotides that are recognized by HIV integrase and that inhibit both the 3'-processing and strand transfer steps involved in the incorporation of viral DNA into human DNA. In addition, these compounds exhibit resistance to degradation by nucleases. If this were not to be the case, these molecules would not be of therapeutic significance. This renewal proposal moves the project into the next phase of development which includes both new synthesis and comprehensive in vitro anti-HIV studies of nuclease-resistant, sequence-specific dinucleotides and their pro-drugs that are stereochemical and regiochemical analogs of the newly discovered inhibitors. One goal of the proposed work is to increase the activity (IC50) against integrase from the low micromolar into the nanomolar range, which would be therapeutically very significant. The planned in vitro anti-HIV studies include wild-type HIV and drug- resistant HIV isolates, as well as drug combination studies. It should be stated that correlation of nucleoside stereochemistry with inhibition of HIV reverse transcriptase by the corresponding triphosphates led to the discovery of some clinically useful anti-AIDS agents. Related reasoning and current data strongly suggest that conformational and configurational factors, as well as base sequence recognition, may be of critical importance in the discovery of therapeutically significant anti-AIDS dinucleotides that are directed at HIV integrase. This is a significant focus of the current proposal.

HIV的pol1基因编码病毒复制的三个关键酶。其中两种酶，HIV逆转录酶(RT)和HIV蛋白水解酶，在临床有用的抑制剂方面受到了相当大的关注。相比之下，POL基因的第三种酶，艾滋病毒整合酶，受到的关注要少得多。目前还没有治疗艾滋病的药物，其作用机制是抑制HIV整合酶。整合过程对艾滋病毒复制是必不可少的，在人类细胞中没有与艾滋病毒整合酶功能相当的东西。显然，有关该酶抑制剂的新信息在抗艾滋病毒药物发现领域具有至关重要的作用。这项研究项目的长期目标是发现治疗上有用的艾滋病毒整合酶抑制剂。利用有关艾滋病毒整合酶作用机制的知识，在当前的赠款期间已经发现了两种有效的艾滋病毒-1整合酶抑制剂。这些抑制剂是概念上的新型二核苷酸，可被HIV整合酶识别，并抑制病毒DNA进入人类DNA所涉及的3‘-加工和链转移步骤。此外，这些化合物还表现出对核酸酶降解的抗性。如果不是这样，这些分子就不会有治疗意义。这项更新建议使该项目进入下一个开发阶段，其中包括新的合成和全面的体外抗艾滋病毒研究，即耐核酸酶、序列特异性二核苷酸及其前体药物，这些药物是新发现的抑制剂的立体化学和区域化学类似物。拟议工作的一个目标是将针对整合酶的活性(IC50)从低微摩尔范围提高到纳摩尔范围，这将具有非常重要的治疗意义。计划中的体外抗艾滋病毒研究包括野生型艾滋病毒和抗药性艾滋病毒分离株，以及药物组合研究。应该指出的是，核苷立体化学与相应三磷酸盐抑制艾滋病毒逆转录酶的相关性导致了一些临床上有用的抗艾滋病药物的发现。相关的推理和目前的数据有力地表明，构象和构象因子以及碱基序列识别在发现针对HIV整合酶的具有治疗意义的抗艾滋病二核苷酸方面可能具有至关重要的作用。这是当前提案的一个重要重点。