New Inhibitors of HIV Replication

HIV复制的新抑制剂

基本信息

批准号：
7437277
负责人：
Gabriele Varani
金额：
$ 41.58万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7437277
关键词：
Affinity Anti-Retroviral Agents Antiviral Agents Apical Binding Biochemical Genetics Biological Assay Blood Cell Extracts Cells Cellular Membrane Chemistry Complex Cyclic Peptides Development Disruption Dose Drug Delivery Systems Drug Industry Drug resistance Evaluation Funding Gene Expression Genetic Genome Goals Growth HIV HIV Long Terminal Repeat HIV-1 Highly Active Antiretroviral Therapy Human In Vitro Infection Lead Length Lymphocyte Maintenance Methods Modeling Molecular Weight Penetration Peptides Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Proteins Proviruses RNA RNA-Protein Interaction Research Personnel Research Project Grants Resistance Specificity Structure Tars Testing Toxic effect Trans-Activators Transactivation Viral Virus Virus Latency Virus Replication Work base combinatorial combinatorial chemistry cyclin T1 design improved inhibitor/antagonist interest mimetics peptide analog peptidomimetics prevent programs promoter single molecule tat Protein uptake

项目摘要

DESCRIPTION (provided by applicant): The ability of HIV to enter a latent state creates a fundamental obstacle to the eradication of HIV-1 infection by anti-retroviral therapy and has prompted renewed interest in developing inhibitors that block the re-emergence of latent proviruses. The goal of this research project is to discover new antiviral drugs that target the essential interaction between the Human Immunodeficiency Virus (HIV) Tat protein and TAR RNA, which is required to positively regulate transcriptional elongation from the HIV-1 promoter. An inhibitor of the Tat-TAR interaction would be able to block viral replication both in acutely and in chronically infected cells and selectively target the reservoir of slowly replicating viruses that persists in the presence of Highly Active Anti Retroviral Therapy (HAART). In the previous funding period, we utilized a peptidomimetic approach grounded in structure-based design to discover potent inhibitors of the Tat-TAR interaction. The lead peptidomimetic compounds penetrate cellular membranes, inhibit Tat-dependent transactivation in human cells and inhibit viral replication in primary lymphocytes for a variety of strains through a Tat-dependent mechanism. We now propose to: 1. Optimize the activity of the cyclic peptide mimetics of the Tat protein to inhibit the HIV-1 Tat-TAR interaction and Tat activity in cell extracts 2. Extend the peptide to additionally target the interaction of cyclin T1 with the apical loop of TAR RNA, thereby preventing formation of the Tat-TAR-cycT1 ternary complex and recruitment of the Ptef-b kinase by two mechanisms simultaneously 3. Optimize the uptake and cellular localization of the peptidomimetics and evaluate the activity of the lead compounds in functional cell-based assays 4. Evaluate the activity of the lead compounds in inhibiting viral replication and study the emergence of resistance in the virus in the presence of the peptidomimetic inhibitors. The project will provide the information required to guide the pharmacological development of these compounds. We are very confident that highly selective compounds with ICSOs well below 100 nM can be developed in the course of this program.

描述（由申请人提供）：艾滋病毒进入潜在状态的能力为消除抗逆转录病毒疗法消除HIV-1感染的基本障碍，并引起了人们对开发抑制剂的兴趣，从而阻止重新出现潜在的养育病毒。该研究项目的目的是发现针对人类免疫缺陷病毒（HIV）TAT蛋白和TAR RNA之间基本相互作用的新抗病毒药物，这是从HIV-1启动子中积极调节转录伸长所必需的。 TAT-TAR相互作用的抑制剂将能够在急性和慢性感染细胞中阻止病毒复制，并选择性地靶向缓慢复制病毒的储层，这些病毒在存在高度活跃的抗逆转疗法（HAART）的情况下持续存在。在上一个资金期间，我们利用了基于结构设计的肽型方法来发现TAT-TAR相互作用的有效抑制剂。铅肽型化合物可穿透细胞膜，抑制人类细胞中TAT依赖性反式激活，并通过TAT依赖性机制抑制原发性淋巴细胞的病毒复制。现在，我们提出：1。优化TAT蛋白的环状肽模拟物的活性，以抑制细胞提取物中的HIV-1 TAT-TAT相互作用和TAT活性2。扩展肽以靶向细胞周期蛋白T1的相互作用机制同时3。优化肽仪的摄取和细胞定位，并评估基于功能细胞的测定中铅化合物的活性4。评估铅化合物在抑制病毒复制中的活性，并研究肽瘤抑制剂在病毒中的耐药性出现。该项目将提供指导这些化合物的药理开发所需的信息。我们非常有信心，在该程序过程中，可以开发出低于100 nm的ICSO的高度选择性化合物。