Compounds That Inhibit HIV Rev Function

抑制 HIV Rev 功能的化合物

基本信息

批准号：
7184356
负责人：
DAVID M REKOSH
金额：
$ 41.44万
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 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7184356
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

DESCRIPTION (provided by applicant): Most of the current drugs in use for the treatment of AIDS work by targeting the enzymatic activities of the 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 treatment, 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, focusing on 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.

描述（由申请人提供）：目前用于治疗艾滋病的大多数药物都是通过针对 HIV 逆转录酶或蛋白酶的酶活性发挥作用，尽管目前也正在积极开发其他几个靶点。然而，由于耐药病毒的出现通常是治疗的结果，因此仍然非常需要继续寻找针对其他重要的新型病毒活性的替代疗法。 HIV Rev 功能是迄今为止尚未充分利用的抗病毒靶点。为了寻找 Rev 抑制剂，我们最近设计并筛选了 40,000 种化合物。作为这项工作的结果，我们已经鉴定出八种化学上不相关的杂环化合物，它们似乎在 uM 浓度的化合物下抑制 HIV 复制和 Rev 功能。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各种不同 HIV 分离株的能力。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针对 Rev/RRE 途径中的特定步骤，并确定它们对多种 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、毒性或其他不可预见的问题而被证明不适合药物开发，它们也可能为 Rev 功能的持续研究提供重要的实验室工具。此外，在这项工作的过程中，将开发出易于适用于筛选其他候选 Rev 抑制剂的测定方法。具体目标#1：评估这些化合物抑制多种 HIV-1 分离株复制的能力，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：利用各种基于细胞的生化测定来确定化合物在 Rev 途径中发挥作用的精确步骤。具体目标#3：探索对选定 Rev 抑制剂耐药性的发展，描述耐药性的基础并解决交叉耐药性问题。