Biochemical Mechanism of HIV DNA Integration

HIV DNA整合的生化机制

• 批准号: 10402279
• 负责人: Alan N. Engelman
• 金额: $ 67.92万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402279
• 关键词: AIDS/HIV problem; Active Sites; Address; Allosteric Site; Anti-Retroviral Agents; Applications Grants; Binding; Binding Proteins; Binding Sites; Biochemical; Capsid; Catalytic Domain; Cells; Clinic; Clinical; Coin; Color; Competence; Complex; DNA; DNA Integration; Development; Disease; Drug Compounding; Drug Targeting; Drug resistance; Enzymes; Formulation; Funding; Future; Generations; Genes; Genetic Transcription; Goals; Grant; HIV; HIV vaccine; HIV-1; HIV-1 integrase; Image; In Vitro; Incidence; Infection; Integrase; Integrase Inhibitors; Integration Host Factors; Learning; Morphogenesis; Mutation; Output; Paper; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phenocopy; Property; Proviruses; Publications; Regimen; Research; Resistance; Reverse Transcriptase Inhibitors; Ribonucleoproteins; Role; Seminal; Structure; Virion; Virus; Work; antiretroviral therapy; antiviral drug development; burden of illness; clinical development; comparative; dimer; drug action; drug development; inhibitor; lens epithelium-derived growth factor; meetings; mortality; mutant; novel; particle; pleiotropism; pre-clinical; pre-exposure prophylaxis; pyridine; quinoline; success; thienopyridine; transcriptional coactivator p75; viral DNA; virus host interaction; young adult

PROJECT SUMMARY/ABSTRACT HIV/AIDS remains a debilitating disease globally, with infections among young adults in the US in recent years increasing. Although extensive efforts are dedicated to HIV vaccine and cure research, these approaches have yet to yield candidates for routine clinical use. By contrast, combination antiretroviral therapy (cART) has been used to reduce disease burden and mortality since its introduction into the clinic in the mid-1990s. Recommended cART formulations contain an integrase inhibitor that inhibits the enzyme active site and its strand transfer activity (integrase strand transfer inhibitor or INSTI). Despite their resounding success, incidence of resistance to second-generation INSTIs is increasing, and will predictably increase further as these drugs are rolled out for global usage. Paralleling the success of active site and allosteric site inhibitors of the reverse transcriptase enzyme, the clinic will benefit greatly from the addition of a second class of integrase inhibitor, such as allosteric integrase inhibitors (ALLINIs). This grant over the current funding cycle made seminal contributions to understanding the mechanism of action of pre-clinical ALLINI compounds, and such compounds are today in development at pharmaceutical companies. In this grant application we will continue to categorize the mechanism of ALLINI action, which is critical basic information required in advance of clinical rollout and clinical drug resistance. This research will in part be focused on the mechanism of action of the integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75, which helps to guide the virus to active genes for integration. In particular, some of the best-studied ALLINI chemotypes are effective inhibitors of the LEDGF/p75-integrase binding interaction. Inspired by the success of LEDGF/75 binding site ALLINI compounds, we will now characterize in detail interactions of additional host factors that are shown to bind integrase. As evidenced by the large variety of mutations that cause pleiotropic replication catastrophe, HIV-1 integrase is extremely sensitive to change. Characterization of novel host factor-integrase complexes will define new targets for future antiretroviral inhibitor development.

项目概要/摘要 艾滋病毒/艾滋病在全球范围内仍然是一种使人衰弱的疾病，近年来美国年轻人中出现感染艾滋病毒/艾滋病的情况 增加。尽管人们为艾滋病毒疫苗和治疗研究做出了广泛的努力，但这些方法已经 尚未产生用于常规临床使用的候选药物。相比之下，联合抗逆转录病毒疗法（cART）已 自 20 世纪 90 年代中期引入临床以来，用于减少疾病负担和死亡率。 推荐的 cART 配方含有整合酶抑制剂，可抑制酶活性位点及其活性 链转移活性（整合酶链转移抑制剂或 INSTI）。尽管他们取得了巨大的成功， 第二代 INSTI 耐药性的发生率正在增加，并且预计将进一步增加 这些药物已推出供全球使用。与活性位点和变构位点抑制剂的成功相媲美 逆转录酶，临床将因添加第二类整合酶而受益匪浅 抑制剂，例如变构整合酶抑制剂(ALLINI)。这笔赠款在当前资助周期内 对理解临床前 ALLINI 化合物的作用机制等做出了开创性贡献 目前，制药公司正在开发化合物。在此拨款申请中，我们将继续 对ALLINI作用机制进行分类，这是临床前所需的关键基础信息 推广和临床耐药性。这项研究将部分集中于作用机制 整合酶结合蛋白晶状体上皮衍生生长因子 (LEDGF)/p75，有助于引导病毒 整合的活性基因。特别是，一些研究最充分的 ALLINI 化学型是有效的抑制剂 LEDGF/p75-整合酶结合相互作用的研究。受到 LEDGF/75 结合位点 ALLINI 成功的启发 化合物，我们现在将详细描述显示结合的其他宿主因子的相互作用 整合酶。正如导致多效性复制灾难的多种突变所证明的那样，HIV-1 整合酶对变化极其敏感。新型宿主因子-整合酶复合物的表征将 确定未来抗逆转录病毒抑制剂开发的新目标。