Chemical Fingerprinting

化学指纹图谱

基本信息

批准号：
8786204
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/8786204
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 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 public health relevance repaired stem 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，但亨廷顿疾病（HD）或其他神经退行性疾病尚无有效的治疗方法。高清毒性的原因知之甚少，并且没有明确定义的药物靶标。因此，处于危险和影响的个体无可避免地朝着临床疾病迈进，这不仅提供了疾病的疗法，而且还提供了生物标志物来预测治疗结果的进展。在最后一个资金期间，我们发现了一个有毒的氧化循环，其中突变HD蛋白与引起毒性的扩张突变之间存在合作。毒性发生在四个步骤中，我们为每个步骤开发了有希望的抑制剂。最有希望的化合物XJB-5-131具有线粒体靶向抗氧化特性。尽管它的可溶性很差，但仅给药可以减轻HHDH150Q小鼠模型的HHDH150Q小鼠模型中所有明显的病理特征。 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断裂并停止DNA中的CAG三核苷酸膨胀，（3）靶向MSH2-MSH3的HDAC抑制剂，该蛋白稳定DNA环以创建膨胀。在AIM 1中，我们建议与至少一种抑制剂共同辅助我们最成功的化合物XJB-5-131，以确定药理学，模拟给药的最佳途径，每个抑制剂组合的最大耐受剂量，并根据最佳药物类似药物的剂量在体内进行优先测试。在AIM 2中，我们将使用简单的运动功能，认知，组织病理学和线粒体活性的体内终点测试多击处理的功效，以遵循治疗进展。我们将确定由于突变体HD蛋白的表达，哪种化合物的组合最有效地抵消了毒性。总而言之，没有HD或方法可以加快搜索治疗剂的疗法。迫切需要新的工具和方法。我们新颖的发现化合物和治疗的多击策略提供了一种有希望的治疗方法，需要进一步测试以填补这些医疗空白。