HIV-1 Integrase Structural Biology

HIV-1 整合酶结构生物学

• 批准号: 8429483
• 负责人: Alan N. Engelman
• 金额: $ 45.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429483
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Adenine; Adopted; Basic Science; Binding; Catalysis; Clinical; Collaborations; Complex; Cytosine; DNA; DNA Binding; DNA Integration; DNA Structure; Development; Drug Design; Drug Industry; Drug Interactions; Drug Targeting; Drug resistance; Enzymes; Future; Grant; Guanosine; HIV; HIV-1; Highly Active Antiretroviral Therapy; Human; In Vitro; Integrase; Integrase Inhibitors; Ions; Knowledge; Learning; Length; Life Cycle Stages; Light; Modeling; Molecular Models; Mutation; Oxygen; Patients; Pharmaceutical Preparations; Protease Inhibitor; Protein Chemistry; Proteins; RNA-Directed DNA Polymerase; Resistance; Retroviridae; Reverse Transcription; Role; Scientist; Spumavirus; Structure; Therapeutic Intervention; Variant; Viral; Virus Diseases; Work; X-Ray Crystallography; base; design; divalent metal; drug structure; inhibitor/antagonist; molecular modeling; next generation; novel; pathogen; prototype; resistant strain; scaffold; structural biology; success; three dimensional structure; viral DNA

DESCRIPTION (provided by applicant): Integration, catalyzed by the viral integrase protein, is an essential step in the life cycle of all retroviruses. This has highlighted the human immunodeficiency virus type 1 (HIV- 1) integrase protein as an important target for therapeutic intervention, and the first integrase inhibitor, raltegravir, was approved for use with AIDS patients in 2007. Because raltegravir-resistance arises in patients, there is an ongoing, important need to develop next generation inhibitors that will work to counteract drug-resistant strains, and this work is underway in the pharmaceutical industry. Such drug design efforts are helped significantly by knowledge of detailed structures of the targeted protein, as well as structures of drug-bound complexes. Drugs like raltegravir preferentially bind to and inhibit the integrase-DNA complex or intasome that forms after reverse transcription as compared to the free integrase protein, highlighting the crucial need for structural information on the HIV-1 intasome. Until recently, there was no experimentally derived structure for any retroviral intasome, but work conducted during the ongoing grant platform culminated in solving the x-ray crystal structure of the prototype foamy virus (PFV) intasome. To begin to understand the analogous HIV-1 structure, we have built a molecular model using the PFV structure as a scaffold, and work proposed herein will evaluate numerous integrase-DNA contacts unveiled in the model for their roles in integration in vitro and during virus infection. We moreover will adopt what we have learned during our extensive studies with PFV and apply this knowledge to solve the three-dimensional structure of the HIV-1 intasome. The HIV-1 structure will be an invaluable asset for basic research as well as clinical scientists, as it will define the structural basis of HIV-1 DNA integration and provide a crucial platform for development of next generation integrase inhibitors.

描述（由申请人提供）：由病毒整合酶蛋白催化的整合是所有逆转录病毒生命周期中的重要步骤。这凸显了人类免疫缺陷病毒1型（HIV-1）整合酶蛋白作为治疗干预的重要靶点，第一个整合酶抑制剂拉替拉韦于2007年被批准用于艾滋病患者。由于患者对拉替拉韦产生耐药性，目前迫切需要开发下一代抑制剂来对抗耐药菌株，这项工作正在制药行业进行。了解目标蛋白的详细结构以及药物结合复合物的结构对此类药物设计工作有很大帮助。与游离整合酶蛋白相比，拉替拉韦等药物优先结合并抑制逆转录后形成的整合酶-DNA 复合物或整合体，这凸显了对 HIV-1 整合体结构信息的迫切需要。直到最近，还没有任何逆转录病毒嵌体的实验衍生结构，但在正在进行的资助平台期间进行的工作最终解决了原型泡沫病毒 (PFV) 嵌体的 X 射线晶体结构。为了开始了解类似的 HIV-1 结构，我们使用 PFV 结构作为支架建立了一个分子模型，本文提出的工作将评估模型中揭示的众多整合酶-DNA 接触点，了解它们在体外整合和病毒传播过程中的作用感染。此外，我们将采用我们在 PFV 广泛研究中所学到的知识，并将这些知识应用于解决 HIV-1 嵌体的三维结构。 HIV-1结构将成为基础研究和临床科学家的宝贵财富，因为它将定义HIV-1 DNA整合的结构基础，并为下一代整合酶抑制剂的开发提供重要平台。