Pharmacology of HIV Viral DNA & Retroviral Integrases

HIV病毒DNA的药理学

• 批准号: 7048180
• 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/7048180
• 关键词: DNA binding protein; DNA replication; Retroviridae; antiAIDS agent; binding sites; cations; crosslink; drug screening /evaluation; electron crystallography; enzyme inhibitors; enzyme mechanism; enzyme structure; enzyme substrate complex; human immunodeficiency virus 1; integrase; intermolecular interaction; ketones; pharmacokinetics; protein structure function; recombinant proteins; site directed mutagenesis; virus DNA; virus infection mechanism; virus integration; virus protein

To extend the target range for development of anti-retroviral agents, we are focusing on HIV-1 integrase inhibitors using recombinant enzyme and short oligonucleotides corresponding to the proviral ends (LTR's). Integrase is a rationale target for drug development because it is essential for viral replication. It is encoded by HIV and does not have a cellular equivalent. Our laboratory has pioneered the integrase inhibitors research field, discovered several families of lead inhibitors and patented some with the aim of therapeutic development. 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 elucidate the molecular pharmacology of the DKA, and more specifically their binding site in the integrase-DNA complex. We are performing structure-activity relationship and collaborating with David Davies' crystallography group (NIDDK). 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 our derivatives. We recently found in collaboration with Dr. Peter Roller (Laboratory of Medicinal Chemistry, CCR, NCI) that cationic peptides derived from indolicidin are integrase inhibitors. Their mechanism of action is novel as they bind to DNA, and thereby interfere with the formation of competent integrase-DNA complexes. In parallel, we are studying the molecular interactions between integrase and its DNA substrate using site-directed mutagenesis and enzyme-DNA crosslinking assays.

为了扩大抗逆转录病毒药物开发的目标范围，我们将重点放在使用重组酶和对应于原病毒末端（LTR）的短寡核苷酸的 HIV-1 整合酶抑制剂上。整合酶是药物开发的合理靶点，因为它对于病毒复制至关重要。它由 HIV 编码，没有细胞等效物。我们的实验室开创了整合酶抑制剂研究领域，发现了几个先导抑制剂家族，并为一些药物申请了专利，以用于治疗开发。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 整合酶抑制剂已进入临床试验。我们正在与 Terrence Burke 博士（CCR、NCI 药物化学实验室）和 Vinay Pathak 博士（CCR、NCI 抗病毒耐药项目）合作研究这些二酮酸 (DKA) 衍生物。我们的目标是阐明 DKA 的分子药理学，更具体地说是阐明它们在整合酶-DNA 复合物中的结合位点。我们正在研究构效关系，并与 David Davies 的晶体学小组 (NIDDK) 合作。我们发现二酮酸的叠氮基衍生物是有效的、选择性的抗整合酶抑制剂，并且具有抗病毒作用。我们的衍生物已申请专利。我们最近与 Peter Roller 博士（CCR、NCI 药物化学实验室）合作发现，源自 indolicidin 的阳离子肽是整合酶抑制剂。它们的作用机制很新颖，因为它们与 DNA 结合，从而干扰有效整合酶-DNA 复合物的形成。与此同时，我们正在利用定点诱变和酶-DNA 交联测定来研究整合酶与其 DNA 底物之间的分子相互作用。