Viral Replication Inhibitors Targeted at HIV Integrase

针对 HIV 整合酶的病毒复制抑制剂

• 批准号: 6409073
• 负责人: VASU NAIR
• 金额: $ 25.73万
• 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 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6409073
• 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基因编码三种病毒复制的关键酶。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得到了相当多的关注。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。目前临床上还没有一种药物的作用机制是抑制HIV整合酶。整合过程对HIV复制至关重要，并且在人类细胞中没有功能等同的HIV整合酶。很明显，这种酶抑制剂的新信息在抗hiv药物发现领域是至关重要的。这个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。利用对HIV整合酶作用机制的了解，在目前的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与人类DNA结合过程中的3'加工和链转移步骤。此外，这些化合物表现出抗核酸酶降解的能力。如果不是这样，这些分子就不会有治疗意义。这一更新提议将项目推进到下一个发展阶段，其中包括新的合成和全面的体外抗hiv研究，耐核酸酶，序列特异性二核苷酸及其前药是新发现抑制剂的立体化学和区域化学类似物。提出的工作的一个目标是将抗整合酶的活性（IC50）从低微摩尔提高到纳摩尔范围，这将在治疗上非常重要。计划进行的体外抗HIV研究包括野生型HIV和耐药HIV分离株，以及药物联合研究。应该指出的是，核苷立体化学与相应的三磷酸盐抑制HIV逆转录酶的相关性导致了一些临床有用的抗艾滋病药物的发现。相关推理和目前的数据强烈表明，构象和构型因素以及碱基序列识别可能对发现针对HIV整合酶的具有治疗意义的抗艾滋病二核苷酸至关重要。这是当前提案的一个重要焦点。