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DEVELOPMENT OF NEW APPROACHES TO INHIBIT GROWTH OF HIV

开发抑制艾滋病病毒生长的新方法

基本信息

批准号：
2376383
负责人：
PATRICK O. BROWN
金额：
$ 20.65万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-03-01 至 1998-02-28
项目状态：
已结题

项目摘要

The early intracellular events in human immunodeficiency virus (HIV) infection, leading to the establishment of the integrated provirus, remain inadequately understood. We hypothesize that many steps in this process, presently unrecognized or unexplored, could provide new targets against which antiviral drugs might be developed. One of the better understood steps in early infection is integration. Integration has clearly been shown to be required for HIV replication, and the biochemistry of integration is understood in broad outline. Yet we are still far from a detailed understanding of integration, and consequently the current approach to developing drugs targeted at integrase may be naive. Indeed, consideration of the place integration occupies in the sequence of events leading to integration in vivo suggests that the most straightforward approach to blocking integration, based on inhibitors of the catalytic activities of integrase, may not be the most effective strategy for preventing its occurrence in an actual infection. The goal of the proposed work is simply to explore and develop the most promising avenues toward discovery of new antiviral agents directed in integration and other early steps in the infection process. Four projects are planned: 1. Continued basic investigations of the biochemistry of integration, aimed at developing a complete description of the regulation, specificity, biochemical mechanism and structure of integrase, and other possible actors in the process. As an integral part of this basic work we will continue to develop assays to test each activity that we can isolate, for possible use in primary or secondary screens of candidate drugs. 2. Exploring new strategies for antiviral agents directed at integrase and testing their feasibility by using mutations in integrase as surrogates for inhibitors. 3. Uncovering new targets for antiviral agents in early infection, using two genetic strategies. We will use a powerful new genetic approach to screen for new mutations in the gag and pol coding regions that impair specific steps in early infection. We will also continue work in progress, using the yeast two-hybrid system to screen for cellular proteins that interact with the Gag or Pol proteins of HIV or murine leukemia virus (MLV). 4. We will define the mechanism of action of integrase inhibitors identified by the ongoing random screens being conducted by the Parke-Davis group.

人类免疫缺陷病毒（HIV）的早期细胞内事件感染，导致整合原病毒的建立，仍然不够了解。我们假设这其中有很多步骤目前尚未认识或未探索的过程可以提供新的目标可能会开发抗病毒药物。较好的之一早期感染的理解步骤是整合。集成有已明确表明是 HIV 复制所必需的，并且整合的生物化学被广泛地理解。然而我们是距离对集成的详细理解还很远，因此目前开发针对整合酶的药物的方法可能是幼稚的。事实上，考虑到整合在导致体内整合的事件顺序表明，最基于抑制剂的阻断整合的直接方法整合酶的催化活性可能不是最有效的防止其在实际感染中发生的策略。拟议工作的目标只是探索和发展最发现新的抗病毒药物的有希望的途径感染过程中的整合和其他早期步骤。四计划项目： 1. 继续进行基础调查整合生物化学，旨在开发完整的描述的调节、特异性、生化机制和结构整合酶以及该过程中其他可能的参与者。作为不可或缺的一部分在这项基础工作中，我们将继续开发分析方法来测试每一项我们可以隔离的活动，可能用于小学或中学候选药物的筛选。 2.探索抗病毒新策略针对整合酶的药物并通过使用测试其可行性整合酶突变作为抑制剂的替代物。 3. 发现新事物使用两种基因来确定早期感染中抗病毒药物的目标策略。我们将使用一种强大的新遗传方法来筛选 gag 和 pol 编码区的新突变会损害特定的早期感染的步骤。我们还将继续进行中的工作，利用酵母双杂交系统筛选相互作用的细胞蛋白与 HIV 或鼠白血病病毒 (MLV) 的 Gag 或 Pol 蛋白结合。 4. 我们将定义已鉴定的整合酶抑制剂的作用机制帕克-戴维斯小组正在进行的随机筛选。