New Inhibitors of HIV Replication

HIV复制的新抑制剂

• 批准号: 6853549
• 负责人: Gabriele Varani
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853549
• 关键词: HIV infections; antiAIDS agent; antiviral agents; biomimetics; biotechnology; chemical structure; combinatorial chemistry; drug discovery /isolation; drug resistance; genetic transcription; host organism interaction; human immunodeficiency virus 1; intermolecular interaction; peptide library; protein protein interaction; small molecule; tissue /cell culture; virus RNA; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): The goal of this research project is to discover new small molecule antiviral drugs that target essential regulatory functions encoded by the Human Immunodeficiency Virus (HIV) viral proteins and RNAs. The HIV-1 genome encodes protein (Tat) and RNA (TAR) elements that positively regulate transcriptional elongation off the HIV-1 promoter. The Rev protein and RRE RNA promote the nucleocytoplamic export of fully spliced viral RNA. If we could inhibit Tat-dependent transactivation of the HIV promoter and Rev dependent mRNA export, it would be possible to shut off viral replication both in acutely and in chronically infected cells. If this was achieved, viral replication within the reservoir of slowly replicating viruses that sustain infection even in the presence of Highly Active Anti Retroviral Therapy (HAART) would be depressed. Compounds that inhibit these viral functions would provide particularly attractive new approaches to combination treatment of drug-resistant HIV-1 strains. We propose to adopt a peptidomimetic approach grounded in structure-based design by pursuing the following specific objectives: 1. Use constrained cyclic peptide mimics of the Tat and Rev proteins to inhibit the HIV-1 Tat-TAR and Rev-RRE interactions; 2. Demonstrate activity of the peptide-like leads in vitro and in cell-based assays for viral replication; 3. Use structure-based drug design methods to reduce the cyclic peptides to potent small molecule mimics using peptidomimetic concepts. While the project is challenging and partly untested, the introduction of new structures leading to therapeutic options for treating drug-resistant viruses would have substantial impact.

描述（由申请人提供）：该研究项目的目标是发现新的小分子抗病毒药物，其目标是由人类免疫缺陷病毒（HIV）病毒蛋白和 RNA 编码的基本调节功能。 HIV-1 基因组编码蛋白质 (Tat) 和 RNA (TAR) 元件，这些元件可正向调节 HIV-1 启动子的转录延伸。 Rev 蛋白和 RRE RNA 促进完全剪接的病毒 RNA 的核质输出。如果我们能够抑制 HIV 启动子的 Tat 依赖性反式激活和 Rev 依赖性 mRNA 输出，那么就有可能在急性和慢性感染细胞中关闭病毒复制。如果实现了这一点，即使在存在高效抗逆转录病毒疗法（HAART）的情况下，缓慢复制的病毒库中的病毒复制也会受到抑制。抑制这些病毒功能的化合物将为耐药HIV-1毒株的联合治疗提供特别有吸引力的新方法。 我们建议通过追求以下具体目标，采用基于结构设计的肽模拟方法： 1. 使用Tat和Rev蛋白的受限环肽模拟物抑制HIV-1 Tat-TAR和Rev-RRE相互作用； 2. 在体外和基于细胞的病毒复制测定中展示肽样先导的活性； 3. 使用基于结构的药物设计方法，利用拟肽概念将环肽还原为有效的小分子模拟物。虽然该项目具有挑战性并且部分未经测试，但引入新结构导致治疗耐药病毒的治疗选择将产生重大影响。