Allele-specific RNA-targeted lead compounds for Huntington's disease

亨廷顿病等位基因特异性 RNA 靶向先导化合物

• 批准号: 9794020
• 负责人: Katherine Deigan Warner
• 金额: $ 20.14万
• 依托单位: RIBOMETRIX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794020
• 关键词: Adopted; Alleles; Binding; Biological Assay; CAG repeat; Calorimetry; Cells; Chemicals; Code; Collaborations; Data; Development; Dimensions; Disease; Disease Progression; Drug Targeting; Elements; Ensure; Foundations; Functional disorder; Genes; Genome; Goals; Gold; Huntington Disease; Huntington gene; Immobilization; Individual; Label; Lead; Ligand Binding; Ligands; Maps; Messenger RNA; Microarray Analysis; Microsatellite Instability; Monitor; National Institute of Neurological Disorders and Stroke; Natural Products; Nervous system structure; Neurodegenerative Disorders; Noise; Nucleotides; Pathogenicity; Pathology; Patients; Peptides; Pharmaceutical Chemistry; Phase; Play; Positioning Attribute; Process; Property; Proteins; Protocols documentation; RNA; Reproducibility; Resolution; Ribosomal RNA; Role; Signal Transduction; Site; Specificity; Structure; Structure-Activity Relationship; System; Technology; Therapeutic; Titrations; Transcript; Translating; Translations; Trinucleotide Repeats; Untranslated RNA; Validation; Vision; base; drug discovery; experimental study; follow-up; in vitro Assay; inhibitor/antagonist; innovative technologies; lead candidate; lead optimization; novel; novel therapeutics; polyglutamine; programs; screening; small molecule; small molecule therapeutics; therapeutic development; therapeutic target; three dimensional structure

RNAs are essential for the functioning of a healthy nervous system, but the dysfunction of coding and noncoding RNAs causes many devastating neurodegenerative disorders. In Huntington’s disease, CAGrepeat expansions encode polyglutamine tracts in one allele of the huntingtin gene. Both the CAG repeatcontaining mRNAs and the translated polyQ protein cause pathology. The huntingtin transcript containing expanded CAG repeats adopts a structure distinct from that formed by the normal mRNA, and the unique disease-associated RNA tertiary structure is a prime target for the development of novel therapeutics. RNA is a compelling target for small-molecule drug discovery, and a three-dimensional RNA structure found only in the disease-associated huntingtin mRNA offers an opportunity for the development of allele-specific small molecules. Multiple natural products target ribosomal RNA, establishing proof of concept for RNA as a drug target; however, RNA-targeted drug discovery remains a nascent field. We are ideally positioned to develop, validate, and apply a screening system to identify small-molecule ligands that specifically target the unique tertiary structure adopted by the disease-related huntingtin mRNA. Our proposed screening platform combines an initial very rapid and high-throughput microarray screen with a secondary assay based on SHAPE technology, the gold standard for RNA structure analyses. This platform will include controls that enforce high specificity of ligand for the target RNA. Following successful validation of this platform in the R21 phase, we will apply the platform to identify small molecules that specifically bind to the disease-associated huntingtin allele in the R33 phase. Validation and initial medicinal chemistry development of hit compounds will serve as a foundation for the development of novel therapies for Huntington’s disease with the opportunity to access an unprecedented level of selectivity. The majority of RNAs share broadly similar overall properties, so a strategy that allows RNA to be targeted in a single case will likely allow targeting of diverse therapeutically important RNAs. The long-term vision of Ribometrix is to apply this platform technology to discover small-molecule therapeutics that target functional RNA structures involved in indications for which there are no approved therapies, including Huntington's disease. We are poised to fully validate and apply an efficient and generic approach for RNA-targeted ligand discovery by targeting an RNA structure unique to the pathogenic disease-causing huntingtin allele.

RNA对于健康的神经系统的功能是必不可少的，但是编码和 非编码RNA导致许多破坏性的神经退行性疾病。在亨廷顿病中， 扩增在亨廷顿基因的一个等位基因中编码多聚谷氨酰胺片段。包含CAG重复序列的 mRNA和翻译的polyQ蛋白导致病理学。亨廷顿蛋白转录本含有 扩增的CAG重复序列采用与正常mRNA形成的结构不同的结构， 疾病相关RNA三级结构是开发新疗法的主要目标。 RNA是小分子药物发现的一个引人注目的靶点， 只有在疾病相关的亨廷顿蛋白mRNA的发展提供了一个机会，等位基因特异性 小分子。多种天然产物靶向核糖体RNA，建立了RNA作为一种 然而，RNA靶向药物发现仍然是一个新兴领域。我们的理想定位是 开发、验证和应用筛选系统，以识别特异性靶向的小分子配体 疾病相关亨廷顿蛋白mRNA所采用的独特三级结构。 我们提出的筛选平台结合了最初的非常快速和高通量的微阵列筛选， 基于SHAPE技术的二次分析，是RNA结构分析的金标准。这 平台将包括实施配体对靶RNA的高特异性的对照。成功后 为了在R21阶段验证该平台，我们将应用该平台来识别 在R33期特异性结合疾病相关的亨廷顿蛋白等位基因。验证和初始药物 hit化合物的化学开发将为开发新的治疗方法奠定基础。 为亨廷顿病提供了前所未有的选择性。 大多数RNA具有大致相似的总体特性，因此， 在单一情况下将可能允许靶向不同的治疗上重要的RNA。的长期愿景 Ribomeetry是应用这一平台技术来发现小分子治疗剂， RNA结构涉及尚未批准治疗的适应症，包括亨廷顿病 疾病我们准备充分验证和应用一种有效和通用的RNA靶向方法， 通过靶向致病性亨廷顿蛋白等位基因特有的RNA结构来发现配体。