靶向 CUG 扩张治疗强直性肌营养不良-猫眼课题宝

靶向 CUG 扩张治疗强直性肌营养不良

批准号：

8530952

负责人：

Paul Hergenrother

金额：

$28.98万

依托单位：

UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN

依托单位国家：

美国

项目类别：

财政年份：

2009

资助国家：

美国

项目状态：

已结题

起止时间：

2009-09-01 至 2015-08-31

来源：

https://reporter.nih.gov/project-details/8530952

关键词：

3&apos Untranslated Regions Adult Affect Affinity Amino Acids Architecture Area Binding Binding Sites Cataract Cell Culture Techniques Cell physiology Cells Client Combinatorial Synthesis Complex Congenital Heart Defects DNA Development Diffuse Disease Disease Progression Docking Elements Evaluation Genes Genetic Genetic Transcription Goals Hereditary Disease Human In Vitro Individual Intercalating Agents Investigation Knowledge Libraries Ligand Binding Ligands Link Mediating Methods Modeling Molecular Muscle Weakness Myotonic Dystrophy Neuromuscular Diseases Nuclear Pathogenesis Peptides Pharmaceutical Chemistry Pre-Clinical Model Protein Binding Protein Isoforms Protein Kinase Proteins RNA RNA Binding RNA Sequences RNA Splicing Research Research Personnel Role S Phase Series Site Solid Specificity Structure Symptoms Therapeutic Intervention Triplet Multiple Birth Variant Vertebral column Work Zinc Fingers base design disease phenotype fetal gain of function high throughput screening mRNA Precursor neuromuscular novel prevent prototype research study scaffold small molecule stoichiometry treatment strategy

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DESCRIPTION (provided by applicant): Mytotonic dystrophy 1 (DM1) is a prevalent neuromuscular disorder that is caused by a poly-CTG expansion in the 3'-untranslated region of the myotonic protein kinase gene (DMPK). This disease cannot be cured, and there are no treatment options that delay disease progression. There is now strong evidence supporting a toxic gain-of-function role for the poly(CUG)RNA sequences (that result upon transcription of the poly-CTG expansion) as the molecular basis for DM1. The poly(CUG)RNA binds to and sequesters important proteins, inhibiting their normal function. Chief among these proteins is muscleblind-like protein 1 (MBNL1), which acts to mediate proper pre-mRNA splicing of several important client pre-mRNAs. As a result of the sequestration of MBNL1 by poly(CUG)RNA, fetal splice variants of at least six key proteins are produced in the adult, leading directly to the disease symptoms. There is considerable genetic evidence that disruption of the MBNL1-poly(CUG)RNA interaction will reverse DM1. Thus, the overall goal of this proposal is to identify and develop small molecules capable of disrupting poly(CUG)RNA-MBNL1 interactions and reversing the DM1 disease phenotype. The key to this approach is that the small molecules must target the RNA, rather than MBNL1, because MBNL1 must be able to act normally in the cell. The poly(CUG)RNA is a good target for the development of small molecule binders because poly(CUG) forms a structured, stable hairpin and CUG repeat sequences are not part of the normal functioning of the cell. Thus, specific targeting of this RNA sequence should disrupt interactions with MBNL1 without affecting other essential cellular processes. The specific aims of the proposal are: 1) to probe the binding affinity and specificity of MBNL proteins for poly(CUG)RNA, 2) the identification of small-molecule binders of poly(CUG)RNA, and 3) the assessment of compounds that disrupt the poly(CUG)RNA-MBNL1 interaction in vitro and in cell culture models of myotonic dystrophy. By pursuing these aims, our goal is to rapidly validate poly(CUG)RNA as a target for the treatment of DM1, and to identify compounds that will be appropriate for medicinal chemistry optimization and evaluation in pre-clinical models of DM1.

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