Compounds That Inhibit HIV Rev Function

抑制 HIV Rev 功能的化合物

基本信息

批准号：
7341584
负责人：
DAVID M REKOSH
金额：
$ 40.65万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341584
关键词：
Acquired Immunodeficiency Syndrome Address Alternative Therapies Antiviral Agents Award Binding Biochemical Biological Assay Cells Data Development Endopeptidases Evaluation Funding Goals HIV HIV-1 Heterocyclic Compounds Intellectual Property Laboratories Lead Length Mason-Pfizer monkey virus Modality National Institute of Allergy and Infectious Disease Nuclear Pathway interactions Peptide Hydrolases Pharmaceutical Preparations RNA-Directed DNA Polymerase Range Research Project Grants Resistance Resistance development Rights Screening procedure Series Specificity Testing Therapeutic Index Time Toxic effect Transplantation Universities Variant Viral Viral Physiology Virginia Virus Virus Replication Work base cytotoxicity design drug development drug resistant virus inhibitor/antagonist innovation novel novel virus rev Genes small molecule tool trafficking

项目摘要

Most of the current drugs in use for the treatment of AIDS work by targeting the enzymatic activities of :he HIV reverse transcriptase or protease, although presently there is also active development of several other targets. However, because the emergence of drug resistant virus commonly occurs as the result of reatment, there remains a great need to continue the search for alternative therapies that target other essential novel viral activities. HIV Rev function represents a heretofore under-exploited anti-viral target. To find Rev inhibitors, we recently designed and performed a screen of 40,000 compounds. As a result of this work, we have identified eight chemically unrelated heterocyclic compounds that appear to inhibit HIV replication and Rev function at uM concentrations of compound. We now propose to further characterize these small molecule inhibitors, focusingon 3 or 4 of the 8 compounds that our preliminary data suggest are the most promising. We will critically evaluate each compound with respect to its modality of action and ability to target a wide range of different HIV isolates. Our main goal is to unequivocally determine if any of these compounds target a specific step in the Rev/RRE pathway, and to define their inhibitory profile on a wide range of HIV isolates. This data will allow us to judge if further pursuit of these compounds, as lead drug candidates, is warranted. However, even if these compounds turn out to be unsuitable for drug development because of potency, toxicity or other unforeseen issues, they may provide important laboratory tools for continued studies on Rev function. Furthermore, during the course of this work, assays will be developed that would be readily adaptable for screening of other candidate Rev inhibitors. Specific Aim #1: To assess the ability of the compounds to inhibit replication of a broad range of HIV-1 isolates, and to compare their effects on Rev function from the various HIV-1 groups and clades. Specific Aim #2: To utilize a variety of cell-based and biochemical assays to determine the precise step in the Rev pathway where the compounds act. Specific Aim #3: To explore the development of resistance to selected Rev inhibitors, to characterize the basis of resistance and to address the issue of cross-resistance.

目前用于治疗艾滋病的大多数药物都是通过靶向酶活性来发挥作用的。：HIV逆转录酶或蛋白酶，尽管目前也有几种正在积极开发其他目标。然而，由于耐药病毒的出现通常是由于治疗方面，仍然非常需要继续寻找针对其他疾病的替代疗法重要的新型病毒活性。 HIV Rev 功能是迄今为止尚未充分利用的抗病毒靶点。为了找到 Rev 抑制剂，我们最近设计并进行了 40,000 种化合物的筛选。这项工作的结果是，我们确定了八种化学上不相关的杂环化合物似乎可以抑制 HIV 复制和 Rev 功能化合物的 uM 浓度。我们现在建议进一步表征这些小分子抑制剂，重点关注我们的初步数据表明最有希望的 8 种化合物中的 3 或 4 种。我们将严格评估每种化合物的作用方式和针对广泛目标的能力不同的艾滋病病毒分离株。我们的主要目标是明确确定这些化合物中是否有任何一种靶向 Rev/RRE 途径中的具体步骤，并确定其对多种 HIV 分离株的抑制谱。这些数据将使我们能够判断是否有必要进一步研究这些化合物作为主要候选药物。然而，即使这些化合物因效力而被证明不适合药物开发，毒性或其他不可预见的问题，它们可能为 Rev 的继续研究提供重要的实验室工具功能。此外，在这项工作的过程中，将开发出易于使用的分析方法适用于筛选其他候选 Rev 抑制剂。具体目标#1：评估化合物抑制多种 HIV-1 复制的能力分离株，并比较它们对不同 HIV-1 群体和进化枝 Rev 功能的影响。具体目标#2：利用各种基于细胞和生化的检测来确定精确的步骤化合物发挥作用的 Rev 途径。具体目标#3：探索对选定 Rev 抑制剂耐药性的发展，表征耐药性的基础并解决交叉耐药性问题。