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Preclinical Development of Lead Compounds Targeting Myotonic Dystrophy

针对强直性肌营养不良的先导化合物的临床前开发

基本信息

批准号：
8109327
负责人：
Benjamin L Miller
金额：
$ 15.45万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109327
关键词：
Adult Affect Affinity Amides Amino Acids Antisense Oligonucleotides Area Binding Biological Assay Cell Line Cell physiology Cells Cellular Assay Clinical Clinical Research Clonal Expansion Communities Competitive Binding Development Disease Dissociation Diversity Library Ensure Exhibits Fibroblasts Fluorescence Fluorescence Polarization Goals Hand Human In Vitro Individual Laboratories Lead Libraries Link Luciferases Methods Methylation Modeling Modification Molecular Weight Mus Muscle Muscular Dystrophies Myoblasts Myotonic Dystrophy Neuromuscular Diseases Nuclear Oligonucleotides Patients Peptides Performance Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Probability Production Property Protein Splicing Proteins RNA RNA Binding RNA Splicing Relative (related person)Research Research Personnel Screening procedure Series Specificity Structure Symptoms Testing Therapeutic Agents Titrations Toxic effect Transfer RNA Transgenic Mice Translational Research United States National Institutes of Health Untranslated Regions Weight Gain Yeasts analog base cost design high throughput screening improved in vivo inhibitor/antagonist mouse model novel pre-clinical public health relevance research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): Sequestration of MBNL1 by (CUG) repeat RNA is believed to be a key molecular interaction in type 1 myotonic dystrophy (DM1). Thus, new compounds able to inhibit this interaction constitute important potential leads towards the development of effective therapeutic agents. We recently described the discovery of a set of compounds able to bind (CUG) repeat RNA with significant selectivity and inhibit MBNL1 binding. Our proposed research centers on three Aims that will expand on this important initial result, and obtain compounds suitable for clinical development. First, we will determine the minimum binding peptide capable of maintaining selective (CUG) repeat RNA binding, and will explore the effect of peptide N-methylation on affinity. Second, we will employ the highest-affinity lead compound in a displacement-based high throughput screen for new (CUG) repeat-binding chemotypes. Finally, we will carry out a series of cellular assays to determine the ability of new compounds to inhibit (CUG) RNA - MBNL1 binding in a cellular context. PUBLIC HEALTH RELEVANCE: Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting 1 in 8000 people. The disease is believed to result from the accumulation of a toxic RNA, termed a "CUG repeat", which sequesters a protein critical for proper cellular function. Building on a discovery made in our laboratory of a molecule able to bind CUG repeat RNA, we will carry out a series of experiments designed to yield a new molecule with higher activity and improved drug-like properties. The overall goal of the project will be to obtain at least one compound suitable for development as a therapeutic agent.

描述（由申请人提供）：（CUG）重复RNA对MBNL 1的隔离被认为是1型强直性肌营养不良（DM 1）中的关键分子相互作用。因此，能够抑制这种相互作用的新化合物构成了开发有效治疗剂的重要潜在线索。我们最近描述了一组化合物的发现，能够结合（CUG）重复RNA具有显着的选择性和抑制MBNL 1结合。我们提出的研究集中在三个目标上，这些目标将扩展这一重要的初步结果，并获得适合临床开发的化合物。首先，我们将确定能够维持选择性（CUG）重复RNA结合的最小结合肽，并将探索肽N-甲基化对亲和力的影响。第二，我们将采用最高亲和力的先导化合物在置换为基础的高通量筛选新的（CUG）重复结合化学型。最后，我们将进行一系列细胞测定以确定新化合物在细胞环境中抑制（CUG）RNA-MBNL 1结合的能力。 1型强直性肌营养不良症（DM 1）是成人肌营养不良症中最常见的形式，每8000人中就有1人受到影响。这种疾病被认为是由一种称为“CUG重复”的有毒RNA的积累引起的，该RNA螯合了一种对正常细胞功能至关重要的蛋白质。在我们实验室发现能够结合CUG重复RNA的分子的基础上，我们将进行一系列实验，旨在产生具有更高活性和改善药物样特性的新分子。该项目的总体目标是获得至少一种适合开发为治疗剂的化合物。