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）：该研究项目的目的是发现新的小分子抗病毒药物，这些药物针对人类免疫缺陷病毒（HIV）病毒蛋白和RNA所编码的基本调节功能。 HIV-1基因组编码蛋白质（TAT）和RNA（TAR）元素，这些元素阳性地调节了HIV-1启动子的转录伸长。 REV蛋白和RRE RNA促进了完全剪接的病毒RNA的核细胞胶质出口。如果我们可以抑制HIV启动子和依赖性mRNA导出的TAT依赖性反式激活，则可以在急性和慢性感染细胞中关闭病毒复制。如果实现这一目标，即使在存在高度活跃的抗逆转录病毒疗法（HAART）的情况下，在储层内的病毒复制也会降低。抑制这些病毒功能的化合物将为抗药性HIV-1菌株的组合提供特别有吸引力的新方法。 我们建议通过追求以下特定目标来采用以结构设计为基础的替代方法： 1。使用受约束的TAT和REV蛋白的循环肽模仿来抑制HIV-1 TAT-TAT和REV-RRE相互作用； 2。证明了肽样的活性在体外和基于细胞的病毒复制的基于细胞的测定中； 3。使用基于结构的药物设计方法将环状肽降低到使用肽概念概念的有效的小分子模仿。尽管该项目具有挑战性且未经过测试，但引入新的结构，导致治疗耐药病毒的治疗选择将产生重大影响。