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New Inhibitors of HIV replication

HIV复制的新抑制剂

基本信息

批准号：
8501111
负责人：
ERIC J ARTS
金额：
$ 41.73万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2006-03-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501111
关键词：
Affinity Anti-Retroviral Agents Antiviral Agents Binding Biochemical Biological Assay CD4 Positive T Lymphocytes Cell model Cells Cellular Membrane ChIP-seq Chemistry Collaborations Complement Complex Cyclic Peptides DNA-Directed RNA Polymerase Development Drug resistance Elements Evaluation Exhibits Funding Gene Expression Generations Genes Genetic Recombination Genetic Transcription Genome Goals Growth HIV HIV-1 Health Highly Active Antiretroviral Therapy Infection Initiator tRNA Latent Virus Lead Lymphocyte Maintenance Measures Messenger RNA Methylation Modification Molecular Mechanisms of Action Molecular Models Molecular Target Mutation Nevirapine Patients Peptides Pharmaceutical Preparations Pharmacology Phase Proteins Proviruses RNA RNA Binding RNA-Directed DNA Polymerase Research Project Grants Resistance Rest Reverse Transcription Reverse Transcription Inhibition Series Side Site Specificity Structural Chemistry Structure Time Trans-Activators Treatment Failure Vertebral column Viral Viral Genes Viral Genome Viral Reverse Transcription Virus Virus Activation Virus Inhibitors Virus Latency Work base conventional therapy design drug candidate drug discovery drug mechanism fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether improved inhibitor/antagonist interest memory CD4 T lymphocyte mimetics molecular modeling mutant novel novel strategies peptidomimetics promoter protein function resistance mutation scaffold stem

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 continued interest in developing inhibitors that block the re-emergence of latent proviruses. The goal of this research project is to continue the development of new antiviral leads that target the HIV TAR RNA, and inhibit at the same time reverse transcription and transcriptional elongation from the HIV-1 promoter. Such an inhibitor would be able to block viral replication in both acutely and chronically infected cells and 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 have identified a new cyclic peptide lead that binds to the HIV TAR RNA with unprecedented activity by expanding peptide chemistry to include un-natural peptidic side chains. The lead peptidomimetic compounds penetrate cellular membranes and inhibit viral replication in primary lymphocytes with activity comparable to nevirapine. We have demonstrated that the antiviral activity coincides with inhibition of both reverse transcription and transcriptional elongation. We now propose to: 1. Optimize the antiviral activity of the cyclic peptide mimetics of the Tat protein to inhibit the function of TARby exploiting additional un-natural peptide side chains and modifications of the peptide backbone 2. Establish the molecular mechanism of action of the peptide leads 3. Generate resistance mutants to fully validate the molecular targets of these anti-viral leads

描述（由申请人提供）：HIV 进入潜伏状态的能力对通过抗逆转录病毒治疗根除 HIV-1 感染造成了根本障碍，并促使人们持续关注开发阻止潜伏原病毒重新出现的抑制剂。该研究项目的目标是继续开发针对 HIV TAR RNA 的新抗病毒先导化合物，并同时抑制 HIV-1 启动子的逆转录和转录延伸。这种抑制剂能够阻断急性和慢性感染细胞中的病毒复制，并针对在高效抗逆转录病毒疗法（HAART）存在下持续存在的缓慢复制病毒库。在上一个资助期间，我们通过扩展肽化学以包含非天然肽侧链，确定了一种新的环肽先导物，它能够以前所未有的活性与 HIV TAR RNA 结合。先导拟肽化合物可穿透细胞膜并抑制原代淋巴细胞中的病毒复制，其活性与奈韦拉平相当。我们已经证明抗病毒活性与逆转录和转录延伸的抑制同时发生。我们现在建议： 1. 通过利用额外的非天然肽侧链和肽主链的修饰，优化 Tat 蛋白环肽模拟物的抗病毒活性，以抑制 TAR 的功能 2. 建立肽先导的作用分子机制 3. 生成耐药突变体，以充分验证这些抗病毒先导的分子靶点