Integrase Structural Virology

整合结构病毒学

• 批准号: 9440913
• 负责人: Alan N. Engelman
• 金额: $ 53.32万
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9440913
• 关键词: 3-Dimensional; Acquired Immunodeficiency Syndrome; Active Sites; Acute; Anti-HIV Agents; Architecture; Betaretrovirus; Biochemical Genetics; Biological; C-terminal; Centers for Disease Control and Prevention (U.S.); Chemical Warfare; Cleaved cell; Clinical; Complex; Cryoelectron Microscopy; DNA; DNA Binding; DNA Integration; Data; Defect; Development; Dinucleoside Phosphates; Drug Design; Drug Targeting; Enzymes; Funding; Genetic Techniques; Grant; HIV; HIV-1; Highly Active Antiretroviral Therapy; Hydroxyl Radical; In Vitro; Infection; Integrase; Integrase Inhibitors; Life Cycle Stages; Maps; Modeling; Morphogenesis; Mouse Mammary Tumor Virus; Nucleoproteins; Patients; Pharmaceutical Preparations; Phase; Positioning Attribute; Proteins; Reaction; Reporting; Research; Resolution; Retroviridae; Role; SIV; Spumavirus; Structure; Synapses; Therapeutic; Time; Viral; Virion; Vision; Work; clinical development; clinically relevant; human model; hydroxyl group; inhibitor/antagonist; model building; novel; particle; prototype; public health relevance; structural biology; three dimensional structure; three-dimensional modeling; viral DNA; viral RNA; virology

 DESCRIPTION (provided by applicant): Integration, catalyzed by the viral integrase protein, is an essential step in the life cycle of all retroviruses, and the integrase enzyme of human immunodeficiency virus type 1 (HIV-1) is a common target of the highly active antiretroviral therapies that are used to treat AIDS patients. Integrase strand transfer inhibitors (INSTIs) have been in clinical use since 2007, and the prior iteration of this renewal application critically discovered their mechanism of action. The target of the INSTIs is the integrase-viral DNA nucleoprotein complex, also known as the intasome, and the understanding of the mechanism of therapeutic action is greatly facilitated through the study of detailed 3- dimensional structure of drug targets. Although a high-resolution structure of the HIV-1 intasome has yet to be reported, we have reported numerous structures for the prototype foamy virus (PFV) intasome, which is also inhibited by the INSTIs. Using this model, we previously described that INSTIs work by ejecting the critical deoxyadenylate residue of viral DNA and its associated 3'-hydroxyl nucleophile from the integrase active site, disarming the integration machinery. During the current funding period we extended this observation to discover that INSTIs are structural mimics of the chemical attacking and leaving groups of the DNA strand transfer reaction. Herein we provide preliminary data for a new retroviral intasome structure, and we will use this new structural information together with the structure of the PFV intasome to refine our working model of the HIV-1 intasome, the clinically relevant INSTI target. We have discovered that the most intriguing integrase drug class since the INSTIs, the allosteric integrase inhibitors (ALLINIS), inhibits HIV-1 particle maturation, implying a structural role for integrase in HIV-1 particle morphogenesis. The role of integrase in forming the infectious HIV-1 structure will be elucidated using a variety of biochemical and genetic techniques. This line of research will culminate with a biologically realistic model for the HIV-1 intasome to aid novel INSTI development and with an acute vision of the mechanism of ALLINI action, which will inform the clinical development of this new and important anti-HIV drug class.

 描述（通过应用得出）：由病毒整合蛋白催化的整合是luse s生命周期的必不可少的步骤，人类免疫缺陷病毒1型（HIV-1）的整合酶是高度活性抗逆转录病毒的常见靶标二手酶抑制剂（Instis）以来一直在临床中使用，并且此更新施用的先前迭代是临床的。随着intasme和治疗作用的机制非常促进，对药物靶标的详细研究的研究尚未报告。原型泡沫病毒（PFV）内体也受到TIS的抑制。发现thestis是DNA链转移反应的结构模拟物。 ，变构抑制剂（Allinis）抑制HIV-1颗粒成熟n HIV-1颗粒形态发生。对Allini作用的机制的急性视野将为这一新的和重要的抗HIV药物类别的临床发展提供信息。