Therapeutic Mitochondrial Uncouplers

治疗性线粒体解偶联剂

基本信息

批准号：
10398220
负责人：
Webster L Santos
金额：
$ 54.24万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398220
关键词：
2,4-Dinitrophenol Address Affect Animal Model Benchmarking Biological Assay Biopsy Bypass Caymans Cell membrane Characteristics Chemicals Cirrhosis Clinic Clinical Clinical Trials Data Diet Drug Kinetics Ensure Environment Etiology FDA approved Fatty Liver Fatty acid glycerol esters Fibrosis Functional disorder Goals Hepatic High Fat Diet Human Hyperthermia Image In Vitro Inflammation Inner mitochondrial membrane Laboratories Liver Failure Liver diseases Mediating Mitochondria Mitochondrial Matrix Modeling Mus Nature Non-Rodent Model Oral Oxidative Stress Pathology Pathway interactions Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase III Clinical Trials Physiological Population Primary carcinoma of the liver cells Process Production Property Proteins Protons Reactive Oxygen Species Research Research Personnel Safety Source Specificity Streptozocin Structure-Activity Relationship Testing Therapeutic Therapeutic Effect Tissues Toxic effect alkalinity clinically relevant design efficacious treatment efficacy validation fatty liver disease hepatocyte injury improved in vivo in vivo evaluation innovation islet amyloid polypeptide liver inflammation mesoxalonitrile metabolic rate mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics oxidation phase III trial phenylhydrazone preservation prevent programs protein transport response scaffold screening side effect small molecule success tool

项目摘要

PROJECT SUMMARY The goal of this project is to develop small molecule mitochondrial uncouplers for the treatment of non- alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD). Approximately 26 million people (~6-8% of US population) are affected by NASH, and more than 30% of patients with NASH- related cirrhosis will die from liver failure or hepatocellular cancer. There are currently no FDA-approved drugs to treat NASH and the top drugs in clinical trials suffer from ineffectiveness or have unwanted side effects. NASH is characterized by fat accumulation in the liver, inflammation, and tissue remodeling. Mitochondrial uncouplers have strong potential as NASH therapeutics by the nature of their mode of action targeting fat accumulation and oxidative stress. Mitochondrial uncouplers transport protons from the mitochondrial intermembrane space into the matrix bypassing ATP synthase. This process increases fat oxidation and decreases mitochondrial reactive oxygen species production; thereby, directly targeting two pathways that underlie NASH pathophysiology that drive inflammation and the fibrogenic response. Our laboratories have recently discovered mitochondria- selective, safe, and orally bioavailable mitochondrial uncouplers that have wide therapeutic window. Proof-of- principle studies in an accelerated mouse model of NASH (STAM model) achieved the FDA benchmark for approval of a NASH therapeutic by decreasing the NAFLD Activity Score (NAS) by 2 points, with at least one point coming from two different NAS criteria, and with no worsening of fibrosis. These strong preliminary data support a medicinal chemistry program to improve the drug-like properties of the molecules (Aim 1) and validate molecules in a more physiologically and clinically relevant mouse model of NASH involving Amylin diet (Aim 2). The major innovation of our program is the discovery of novel chemical scaffolds that have different levels of mitochondrial uncoupling capacity that are safe and self-limiting. As there are currently no drugs with a mitochondrial uncoupling as the primary mode of action in the clinic, our program could be the first to deliver mitochondrial uncouplers for the treatment of NASH. Indeed, this project addresses a critical need and will make significant contribution to data supporting the validity of modulating mitochondrial uncoupling for safe and efficacious treatment of NASH.

项目摘要该项目的目的是开发小分子线粒体解偶联剂来治疗非 - 酒精性脂肪性肝炎（NASH），一种非酒精性脂肪肝病（NAFLD）的晚期形式。大约 2600万人（约占美国人口的6-8％）受NASH的影响，纳什（Nash）患者中有30％以上相关的肝硬化将死于肝衰竭或肝细胞癌。目前没有FDA批准的药物在临床试验中治疗NASH和最高药物的效果无效或副作用不良。纳什其特征是在肝脏中积聚脂肪，炎症和组织重塑。线粒体解偶子根据其针对脂肪积累的行动方式具有巨大潜力作为NASH治疗剂的潜力氧化应激。线粒体未偶联剂将质子从线粒体膜间空间传输到矩阵绕过ATP合酶。该过程增加脂肪氧化并减少线粒体反应性氧生产；因此，直接针对纳什病理生理的两种途径驱动炎症和纤维化反应。我们的实验室最近发现了线粒体 - 有选择性，安全和口腔生物利用的线粒体解耦合器，具有较宽的治疗窗口。证明在加速的NASH小鼠模型（Stam模型）中的原理研究实现了FDA基准测试通过将NAFLD活动评分（NAS）降低2分，批准NASH治疗性的批准，至少有一个点来自两个不同的NAS标准，没有纤维化恶化。这些强大的初步数据支持药物化学计划，以改善分子的药物样特性（AIM 1）并验证在涉及淀粉蛋白饮食的NASH的更生理和临床相关的小鼠模型中，分子中的分子（AIM 2）。我们计划的主要创新是发现具有不同水平的新型化学脚手架线粒体解偶联能力是安全且自我限制的。由于目前没有药物线粒体解偶联是诊所中的主要行动方式，我们的计划可能是第一个提供的计划线粒体解耦合纳什的治疗。确实，该项目满足了一个关键的需求，并将成为对支持调节线粒体解偶联的数据有效性的数据有重要贡献纳什的有效待遇。