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

RNA对于健康的神经系统的功能是必不可少的，但编码和 非编码RNA会导致许多毁灭性的神经退行性疾病。在亨廷顿病中，CAGrepeat 扩展编码亨廷顿蛋白基因的一个等位基因中的聚谷氨酰胺区域。CAG重复包含 MRNAs和翻译的PolyQ蛋白导致病理。亨廷顿的成绩单包含 扩增的CAG重复序列采用了与正常mRNA不同的结构，其独特的 疾病相关的RNA三级结构是开发新疗法的主要靶点。 RNA是小分子药物发现的一个引人注目的靶点，并发现了一种三维RNA结构 只有在与疾病相关的亨廷顿蛋白mrna中才提供了发展等位基因特异性的机会。 小分子。多种天然产物靶向核糖体RNA，为RNA作为一种 药物靶点；然而，以RNA为靶点的药物发现仍然是一个新领域。我们处于理想的位置，可以 开发、验证和应用筛选系统来识别特定靶标的小分子配体 疾病相关亨廷顿蛋白基因所采用的独特的三级结构。 我们建议的筛查平台将最初非常快速和高通量的微阵列筛查与 一种基于SHAPE技术的二次分析，这是RNA结构分析的金标准。这 平台将包括对目标RNA实施高特异性配基的控制。以下是成功的 验证该平台在R21阶段，我们将应用该平台来鉴定小分子 在R33期与疾病相关的Huntingtin等位基因特异性结合。验证和初步用药 HIT化合物的化学发展将成为开发新疗法的基础 对于亨廷顿氏病，有机会获得前所未有的选择性水平。 大多数RNA具有大致相似的总体属性，因此允许将RNA作为靶点的策略 在单一情况下，可能会允许靶向不同的治疗重要的RNA。的长期愿景 Ribometrix将应用这一平台技术来发现针对功能的小分子疗法 RNA结构涉及没有批准的治疗方法的适应症，包括亨廷顿氏病 疾病。我们准备充分验证和应用一种针对RNA的高效通用方法 通过靶向致病亨廷顿蛋白等位基因特有的RNA结构发现配体。

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.