Chemical Fingerprinting

化学指纹图谱

基本信息

批准号：
8871571
负责人：
Cynthia Therese McMurray
金额：
$ 54.83万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8871571
关键词：
7,8-dihydro-8-oxoguanine Affect Age Antioxidants Back Binding Biological Markers Boxing CAG repeat Cell Nucleus Cellular Stress Chromatin Loop Clinical Cognition Combined Modality Therapy Complex Cytosine DNA DNA Damage DNA Repair Enzymes DNA glycosylase Disease Drug Targeting Enzymes Excision Functional disorder Funding Genes Goals Guanine Health Histone Deacetylase Inhibitor Histopathology Huntington Disease Impaired cognition Individual Injection of therapeutic agent Intervention Light MSH2 gene MSH3 gene Maximum Tolerated Dose Mediating Medical Metabolism Methods Mismatch Repair Mitochondria Motor Mus Mutation Nature Neurodegenerative Disorders OGG1 gene Outcome Oxygen Peritoneal Pharmaceutical Preparations Pharmacology Phenotype Process Production Property Proteins Pyrones Reactive Oxygen Species Recovery Repair Complex Research Risk Route Site Solubility Somatic Cell Speed Sum Surgical Flaps Testing Therapeutic Therapeutic Intervention Toxic effect Treatment Efficacy Trinucleotide Repeats Vertebral column Widowhood analog base chemical fingerprinting chemical stability combat drug development efficacy testing improved in vivo inhibitor/antagonist mitochondrial genome mouse model mutant neuron loss novel oxidation oxidative DNA damage phosphodiester prevent protein aggregate repaired stem targeted treatment tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Despite years of intense efforts, there has been no effective therapeutic approach for Huntington's disease (HD) or other neurodegenerative diseases. The cause of toxicity in HD is poorly understood, and there is no well-defined drug target. Thus, at-risk and affected individuals inexorably progress toward clinical disease, providing an underlying urgency not only to find therapies for the disease, but also to develop biomarkers to predict the progress of therapeutic outcome. During the last funding period, we have discovered a toxic oxidation cycle in which there is cooperation between the mutant HD protein and the expansion mutation in causing toxicity. Toxicity occurs at four steps, and we have developed promising inhibitors to each one. The most promising compound, XJB-5-131, has a mitochondrial targeted antioxidant properties. Although it is poorly soluble, administration alone alleviates all of the obvious pathological features of disease in an hHdH150Q mouse model for HD. In the renewal, we propose to improve the drug-like properties of XJB-5-131 and use an optimized analog in a "multi-hit" therapy in which multiple steps of the toxic oxidation cycles are targeted simultaneously: (1) a tricyclic pyrone for inhibiting the protein aggregates, (2) inhibitors for 8-oxo-G glycosylase, an enzyme that prevents single strand breaks and stops CAG trinucleotide expansion in DNA, and (3) HDAC inhibitors that target MSH2-MSH3, a protein that stabilizes the DNA loops to create expansions. In Aim 1, we propose to co-administer our most successful compound, XJB-5-131, with at least one of the other inhibitors to determine the pharmacology, the optimal route of analog administration, the maximum tolerated dose of each inhibitor combination, and to prioritize in vivo testing according to the best drug-like properties. In Aim 2, we will test the efficacy of multi-hit treatment using simple in vivo endpoints of motor function, cognition, histopathology, and mitochondrial activity to follow therapeutic progression. We will identify which combination of compounds is most effective in offsetting toxicity due to expression of the mutants HD protein. In sum, there are no therapies for HD or methods to speed up the search for therapeutics. New tools and approaches are desperately needed. Our novel discovered compounds and the multi-hit strategy for therapy provide a promising therapeutic approach that warrants further testing to fill these medical gaps.

描述（由申请人提供）：尽管经过多年的努力，仍然没有针对亨廷顿病（HD）或其他神经退行性疾病的有效治疗方法。 HD 毒性的原因尚不清楚，也没有明确的药物靶点。因此，处于危险中和受影响的个体不可避免地会发展为临床疾病，这不仅迫切需要找到该疾病的治疗方法，而且还需要开发生物标志物来预测治疗结果的进展。在上一个资助期间，我们发现了一个有毒的氧化循环，其中突变的HD蛋白和扩展突变之间存在协同作用，导致毒性。毒性分四个步骤发生，我们针对每个步骤都开发出了有前景的抑制剂。最有前途的化合物 XJB-5-131 具有靶向线粒体的抗氧化特性。尽管其溶解性较差，但单独给药可缓解 hHdH150Q 小鼠 HD 模型中疾病的所有明显病理特征。在更新中，我们建议改善XJB-5-131的类药特性，并在“多重打击”疗法中使用优化的类似物，其中同时针对有毒氧化循环的多个步骤：（1）三环用于抑制蛋白质聚集的吡喃酮，(2) 8-oxo-G 糖基化酶抑制剂，一种防止单链断裂并阻止 DNA 中 CAG 三核苷酸扩增的酶，以及 (3) 靶向的 HDAC 抑制剂MSH2-MSH3，一种稳定 DNA 环以产生扩展的蛋白质。在目标 1 中，我们建议将我们最成功的化合物 XJB-5-131 与至少一种其他抑制剂共同给药，以确定药理学、类似物给药的最佳途径、每种抑制剂组合的最大耐受剂量，并根据最佳药物特性优先考虑体内测试。在目标 2 中，我们将使用运动功能、认知、组织病理学和线粒体活性的简单体内终点来测试多重打击治疗的功效，以跟踪治疗进展。我们将确定哪种化合物组合在抵消突变 HD 蛋白表达引起的毒性方面最有效。总而言之，目前还没有针对 HD 的治疗方法，也没有加速寻找治疗方法的方法。迫切需要新的工具和方法。我们新发现的化合物和多重打击治疗策略提供了一种有前途的治疗方法，值得进一步测试以填补这些医学空白。