A small molecule screen to target viral RNA-protein complexes

针对病毒 RNA-蛋白质复合物的小分子筛选

• 批准号: 7494932
• 负责人: Robert Nakamura
• 金额: $ 23.9万
• 依托单位: ADVANCED GENETIC SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494932
• 关键词: Aminoglycoside Antibiotics; Antiviral Agents; Azithromycin; Biological Assay; Cell Line; Cell Survival; Cells; Class; Clinical; Complex; Development; Disruption; Diversity Library; Dose; Drug Delivery Systems; Drug Kinetics; Evaluation; Exhibits; Genetic; Genetic Transcription; Goals; Government; Grant; HIV; HIV therapy; HIV-1; Lead; Macrolide Antibiotics; Marketing; Molecular; Nuclear Export; Numbers; Outcome; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Preclinical Drug Evaluation; Property; Proteins; Public Health; Purpose; Quantitative Structure-Activity Relationship; RNA; RNA-Protein Interaction; Reporter; Resistance; Role; Screening procedure; Small Business Technology Transfer Research; Standards of Weights and Measures; System; Tars; Testing; Therapeutic; Toxic effect; Toxicity Tests; Translations; Treatment Protocols; Uncertainty; Viral; Virus; Virus Diseases; Virus Inhibitors; Work; advanced system; base; drug discovery; high throughput screening; inhibitor/antagonist; novel; novel therapeutics; small molecule; viral RNA

DESCRIPTION (provided by applicant): There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. RNA-protein complexes represent an important and under utilized drug target. In HIV, the Tat-TAR and Rev-RRE RNA- protein complexes carry out essential roles in RNA transcription and nuclear export respectively. Disruption of these RNA-protein complexes can inhibit viral replication, thus this strategy holds great promise for antiviral drug discovery. Advanced Genetic Systems (AGS) and UCSF have jointly developed a cell- based drug-screening platform to target RNA and RNA-protein complexes. The screening platform was rigorously evaluated with control inhibitors and a pilot screen of 4500 small molecule compounds targeting Rev-RRE. From this screen, we identified novel compounds that specifically target Rev, exhibit low toxicity, display favorable pharmacokinetic properties, and inhibit HIV replication at sub-micromolar IC50s. This result has given us great confidence that we have developed a high-quality, robust screening platform capable of identifying inhibitors of viral RNA-protein targets. We now wish to use our screening platform to carry out expanded screens targeting HIV Rev- RRE and Tat-TAR. We will screen a small molecule diversity library to identify new molecular entities that could form the basis of new classes of anti-HIV therapeutics. PUBLIC HEALTH RELEVANCE: There is significant need to develop new classes of antiviral drugs to combat emerging viral diseases and resistance to older drugs. RNA-protein complexes represent an important and under utilized viral drug target. Disruption of an RNA-protein complex can inhibit viral replication, thus this strategy holds great promise for antiviral drug discovery.

描述（由申请人提供）：鉴于出现了对现有药物方案具有耐药性的病毒，因此对新型HIV疗法存在重大需求。RNA-蛋白质复合物是一种重要且未充分利用的药物靶点。在HIV中，Tat-TAR和Rev-RRE RNA-蛋白质复合物分别在RNA转录和核输出中发挥重要作用。破坏这些RNA-蛋白质复合物可以抑制病毒复制，因此这种策略为抗病毒药物的发现带来了巨大的希望。高级遗传系统（AGS）和UCSF联合开发了一种基于细胞的药物筛选平台，以靶向RNA和RNA-蛋白质复合物。用对照抑制剂和靶向Rev-RRE的4500种小分子化合物的中试筛选对筛选平台进行了严格评估。从这个筛选中，我们鉴定了特异性靶向Rev的新型化合物，其表现出低毒性，显示出有利的药代动力学特性，并在亚微摩尔IC 50下抑制HIV复制。这一结果给了我们很大的信心，我们已经开发出一个高质量、强大的筛选平台，能够识别病毒RNA蛋白靶点的抑制剂。我们现在希望使用我们的筛选平台来进行针对HIV Rev-RRE和Tat-TAR的扩大筛选。我们将筛选一个小分子多样性文库，以确定新的分子实体，这些实体可以形成新的抗HIV治疗药物的基础。 公共卫生关系：非常需要开发新类别的抗病毒药物来对抗新出现的病毒性疾病和对旧药物的耐药性。RNA-蛋白质复合物是一种重要且未充分利用的病毒药物靶点。破坏RNA-蛋白质复合物可以抑制病毒复制，因此这种策略为抗病毒药物的发现带来了巨大的希望。