Biochemical Mechanism of HIV DNA Integration

项目摘要/摘要 艾滋病毒/艾滋病在全球范围内仍然是一种令人衰弱的疾病，近年来美国年轻人中有艾滋病毒感染 越来越多。尽管致力于艾滋病毒疫苗和治愈研究的广泛努力，这些方法已经 尚未产生可供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)已经 自1990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配方包含一种抑制酶活性部位的整合酶抑制剂及其 链转移活性(整合酶链转移抑制物或INSTI)。尽管他们取得了巨大的成功， 对第二代INSTIs的耐药性正在增加，并将预测进一步增加 这些药物是面向全球推出的。与活性中心和变构中心抑制剂的成功平行 逆转录酶，临床上添加第二类整合酶将大有裨益 抑制剂，如变构整合酶抑制剂(ALLINI)。这笔赠款是在本供资周期内提供的 对了解临床前Allini化合物作用机制的开创性贡献等 如今，制药公司正在开发化合物。在这次拨款申请中，我们将继续 对Allini的作用机制进行分类，这是临床之前需要的关键基础信息 推广和临床耐药。这项研究将在一定程度上集中在该药的作用机制上 整合酶结合蛋白晶状体上皮源性生长因子(LEDGF)/p75，有助于引导病毒 整合的活跃基因。特别是，一些研究最深入的Allini化学类型是有效的抑制剂。 LEDGF/p75-整合酶结合作用的研究。受LEDGF/75结合位点Allini成功的启发 化合物，我们现在将详细描述其他宿主因子的相互作用，这些宿主因子被证明结合 整合酶。引起多效性复制灾难的各种突变证明了这一点，HIV-1 整合酶对变化极为敏感。新型宿主因子-整合酶复合体Will 确定未来抗逆转录病毒抑制剂开发的新目标。

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.