Pharmacology of HIV Viral DNA & Retroviral Integrases

HIV病毒DNA的药理学

• 批准号: 6761682
• 负责人: YVES POMMIER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6761682
• 关键词: DNA replication; DNA topoisomerases; Retroviridae; antiAIDS agent; chemical binding; drug interactions; drug screening /evaluation; enzyme inhibitors; enzyme mechanism; enzyme structure; human immunodeficiency virus 1; integrase; intermolecular interaction; pharmacokinetics; polyhydroxy compound; protein structure function; thiazoles; virus DNA; virus infection mechanism; virus integration; virus protein

In an effort to further extend the number of targets for development of anti-retroviral agents, we are studying HIV-1 integrase inhibitors using in vitro assays using recombinant enzyme and short oligonucleotides corresponding to the proviral ends (LTR's). Integrase is a rationale target for inhibitor development because it is essential for viral replication. It is also encoded by HIV and does not have a cellular equivalent. Our laboratory has pioneered this research field and reported various families of inhibitors. Recently, the first class of selective HIV-1 integrase inhibitors with demonstrated antiviral activity related to integrase inhibition has been introduced in clinical trials. We are investigating these diketo acid (DKA) derivatives in collaboration with Dr. Terrence Burke (Laboratory of Medicinal Chemistry, CCR, NCI) and Dr. Vinay Pathak (Antiviral Drug Resistance Program, CCR, NCI). Our goals are to determine the structure-activity relationship for this new type of compounds, to elucidate the drug binding site(s) in the enzyme-DNA complex, and to discover agents with a greater therapeutic index and/or novel structural motifs. We found that azido derivatives of diketo acids are potent and selective anti-integrase inhibitors, and are antiviral. A patent application has been filed for these derivatives. We are also studying novel types of inhibitors that can prevent integration by binding to the proviral DNA ends as well as small peptide and nucleotide inhibitors. We are also studying the molecular interactions between integrase and its DNA substrate using enzyme-DNA crosslinking assays in order to model drug-enzyme-DNA interactions. We recently found a novel interaction between one of the viral DNA bases and the enzyme.

为了进一步扩大抗逆转录病毒药物开发的靶点，我们正在利用重组酶和与前病毒末端(LTR‘s)相对应的短寡核苷酸，在体外试验中研究HIV-1整合酶抑制剂。整合酶是开发抑制剂的基本靶点，因为它对病毒复制是必不可少的。它也是由艾滋病毒编码的，没有细胞上的等价物。我们实验室开创了这一研究领域，并报道了多种抑制剂家族。最近，第一类具有与整合酶抑制相关的抗病毒活性的选择性HIV-1整合酶抑制剂已被引入临床试验。我们正在与特伦斯·伯克博士(药物化学实验室，CCR，NCI)和Vinay Pathak博士(抗病毒耐药性计划，CCR，NCI)合作研究这些二酮基酸(DKA)衍生物。我们的目标是确定这类新型化合物的构效关系，阐明酶-脱氧核糖核酸复合体中的药物结合部位(S)，并发现具有更大治疗指数和/或新结构基序的药物。我们发现二酮酸叠氮衍生物是有效的、选择性的抗整合酶抑制剂，并且具有抗病毒作用。这些衍生品的专利申请已经提交。我们还在研究通过与前病毒DNA末端结合来阻止整合的新型抑制剂，以及小肽和核苷酸抑制剂。我们还利用酶-DNA交联法研究整合酶与其DNA底物之间的分子相互作用，以模拟药物-酶-DNA相互作用。我们最近发现了病毒DNA碱基和酶之间的一种新的相互作用。