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 pol 基因编码病毒复制的三种关键酶。其中两种酶，HIV 逆转录酶 (RT) 和 HIV 蛋白酶；在临床上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 HIV 整合酶受到的关注要少得多。临床上尚无以抑制HIV整合酶为作用机制的治疗艾滋病的药物。整合过程对于 HIV 复制至关重要，并且人体细胞中没有与 HIV 整合酶功能相当的功能。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至关重要。该研究项目的长期目标是发现治疗上有用的 HIV 整合酶抑制剂。利用有关 HIV 整合酶作用机制的知识，在当前资助期内发现了两种有效的 HIV-1 整合酶抑制剂。这些抑制剂是概念上新颖的二核苷酸，可被 HIV 整合酶识别，并抑制病毒 DNA 掺入人类 DNA 所涉及的 3' 加工和链转移步骤。此外，这些化合物表现出对核酸酶降解的抵抗力。如果情况并非如此，这些分子就不具有治疗意义。这项更新提案使该项目进入下一阶段的开发，其中包括新的合成和对核酸酶抗性、序列特异性二核苷酸及其前药的全面体外抗艾滋病毒研究，这些前药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）从低微摩尔提高到纳摩尔范围，这在治疗上非常重要。计划的体外抗HIV研究包括野生型HIV和耐药HIV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的三磷酸酯对HIV逆转录酶的抑制的相关性导致了一些临床上有用的抗艾滋病药物的发现。相关推理和当前数据强烈表明，构象和构型因素以及碱基序列识别对于发现针对HIV整合酶的具有治疗意义的抗艾滋病二核苷酸可能至关重要。这是当前提案的一个重点。