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A Rational Approach to Targeting Unstable RNA Repeats

靶向不稳定 RNA 重复序列的合理方法

基本信息

批准号：
9316040
负责人：
DANITH H LY
金额：
$ 22.36万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316040
关键词：
Acids Adopted Affect Affinity Alleles Amino Acid Sequence Amyotrophic Lateral Sclerosis Ataxia Atrophic Back Base Pairing Binding Binding Sites Biophysics Chemical Structure Code Complex Cytoplasm DNA Development Disease Drug Kinetics Electrophoretic Mobility Shift Assay Fragile X Syndrome Genes Goals Grant Hand Hereditary Disease Huntington gene Hydrogen Bonding Individual Intervention Kinetics Lateral Lead Length Ligand Binding Ligands Machado-Joseph Disease Methods Molecular Mus Muscle Mutation Myotonic Dystrophy Neurodegenerative Disorders Oligonucleotides Pathogenicity Peptides Pharmaceutical Preparations Physiological Production Property Proteins Publishing RNA RNA Splice Sites RNA Splicing Research Research Project Grants Roentgen Rays Route Scheme Sclerosis Series Specificity Spinobulbar Muscular Atrophy Structure TNFSF5 gene Testing Therapeutic Thermodynamics Transcript Translating Tremor Triplet Multiple Birth Ursidae Family Vertebral column X-Ray Crystallography base biophysical techniques blind chemical reaction chemical synthesis citral B design disease phenotype indium arsenide monomer neuromuscular novel nucleobase protein function prototype scale up simulation small molecule therapeutic development therapeutic target therapy development

项目摘要

PROJECT SUMMARY A number of genetic disorders, including myotonic dystrophy (DM1 and DM2), fragile X tremor/ataxia, Huntingtin's disease, Machado-Joseph disease, spinocerebella ataxia, and more recently, amyotrophic lateral sclerosis (ALS, also known in the U.S. as Lou Gehrig's disease), occur as the result of unstable repeat expansion. For many of these repeat sequences, once transcribed they adopt a peculiar hairpin structure that closely resembles the binding site of an RNA splicing factor muscleblind-like 1 (MBNL1) protein. Sequestration of MBNL1 not results in the loss of its function, but also traps the gene transcript from being exported to the cytoplasm and from being translated into a functional protein. It has been demonstrated by several labs that disruption of the RNAexp-MBNL1 complex leads to reversion in the disease phenotype, in particular DM1. While MBNL1 has long been recognized as a bona fide therapeutic target of DM1, it remains a challenge to design molecules that can recognize and bind CUGexp, the cause of DM1, with high affinity, sequence-specificity, and selectivity, and displace MBNL1. The proposed research aims at developing a novel molecular platform for targeting CUGexp, as a proof-of-concept for treating neurodegenerative diseases associated with repeat expansion. Aim 1. Synthesis of chemical building blocks and the corresponding ligands. In the preliminary study we have performed MD simulations and carried out chemical reactions demonstrating the validity of the design concept and the feasibility of the synthetic routes. In the proposed study, we will scale up the monomer production and prepare the corresponding ligands for binding study. Aim 2. Determination of the binding properties of ligands. We will employ an array of biophysical methods, including UV-vis, CD, ITC, SPR, and electrophoretic mobility-shift assays to determine the binding properties of the newly designed ligands. Gaining a full understanding of the binding kinetics and thermodynamics is an important first step toward developing molecular therapies for treating the aforementioned genetic diseases. The proposed molecular design concept is general, applicable not only to targeting CUGexp, but also a slew of other repeated expansion sequences. If successfully developed, the proposed research will have far-reaching implication for the treatment of neurodegenerative diseases associated with repeat expansion.

项目总结