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Viral Replication Inhibitors Targeted at HIV Integrase

针对 HIV 整合酶的病毒复制抑制剂

基本信息

批准号：
6729915
负责人：
VASU NAIR
金额：
$ 25.34万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 2006-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6729915
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

项目摘要

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。目前还没有临床上用于艾滋病的药物，其作用机制是抑制HIV整合酶。整合过程对于HIV复制是必不可少的，并且在人类细胞中没有HIV整合酶的功能等同物。很明显，这种酶的抑制剂的新信息是至关重要的抗艾滋病毒药物发现领域。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HIV整合酶作用机制的知识，在当前的资助期内发现了两种HIV-1整合酶的有效抑制剂。这些抑制剂是概念上新颖的二核苷酸，其被HIV整合酶识别并且抑制涉及病毒DNA掺入人DNA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抗性。如果不是这种情况，这些分子就没有治疗意义。这一更新建议将该项目带入下一个开发阶段，其中包括核酸酶抗性、序列特异性二核苷酸及其前药的新合成和全面的体外抗HIV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。所提出的工作的一个目标是将针对整合酶的活性（IC 50）从低微摩尔增加到纳摩尔范围，这在治疗上是非常重要的。计划的体外抗艾滋病毒研究包括野生型艾滋病毒和耐药艾滋病毒分离株，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抑制HIV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强烈表明，构象和构型因素，以及碱基序列识别，可能是至关重要的治疗显着的抗艾滋病二核苷酸，针对HIV整合酶的发现。这是本提案的一个重要重点。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.

新型抗 HIV 活性整合酶抑制剂的药代动力学和剂量范围发现毒性。

DOI：
10.1016/j.antiviral.2014.05.001
发表时间：
2014
期刊：
Antiviral research
影响因子：
7.6
作者：
Nair,Vasu;Okello,Maurice;Mishra,Sanjay;Mirsalis,Jon;O'Loughlin,Kathleen;Zhong,Yu
通讯作者：
Zhong,Yu

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.